|
1
|
Qin Z, Li Y, Shao X, Li K, Bai Y, Wang B, Ma F, Shi W, Song L, Zhuang A, He F, Ding C, Yang W. HNF4A functions as a hepatocellular carcinoma oncogene or tumor suppressor depending upon the AMPK pathway activity status. Cancer Lett 2025; 623:217732. [PMID: 40254090 DOI: 10.1016/j.canlet.2025.217732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 04/10/2025] [Accepted: 04/17/2025] [Indexed: 04/22/2025]
Abstract
Cancer cells frequently undergo energy metabolic stress induced by the increased dynamics of nutrient supply. Hepatocyte nuclear factor 4A (HNF4A) is a master transcription factor (TF) in hepatocytes that regulates metabolism and differentiation. However, the mechanism underlying how HNF4A functions in cancer progression remains unclear due to conflicting results observed in numerous studies. To address the roles of HNF4A in hepatocellular carcinoma (HCC), we investigated the regulatory functions of HNF4A in HCC cells under different glucose supply conditions. We found that HNF4A exhibited tumor-suppressive effects on the proliferation and migration of HCC cells in glucose-sufficient conditions and tumor-promotive effects on HCC cells in glucose-insufficient conditions. Further investigation revealed that this diverse function of HNF4A was dependent upon the AMPK pathway activity. Similarly, the prognosis predicted by HNF4A was also correlated with whether the AMPKa expression levels were low or high in clinical HCC patients. Multiomics approaches consisting of proteomics and ChIP-seq revealed that key HNF4A target genes, including NEDD4 and RPS6KA2, are involved in the diverse function of HNF4A in HCC in response to the AMPK activity status. Specifically, HNF4A could bind to the promoter region of NEDD4 and RPS6KA2, and upregulating their expression. Our study has demonstrated the relationship between and synergism of AMPK and HNF4A in the progression of HCC under diverse nutrient conditions.
Collapse
Affiliation(s)
- Zhaoyu Qin
- Department of Pediatric Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Yan Li
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Xiexiang Shao
- Department of Pediatric Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Kai Li
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Yihe Bai
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Bing Wang
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Fahan Ma
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Wenhao Shi
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China; School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Lei Song
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Aojia Zhuang
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Fuchu He
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China; School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Chen Ding
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Wenjun Yang
- Department of Pediatric Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| |
Collapse
|
|
2
|
Mohanty SS, Warrier S, Rangarajan A. Rethinking AMPK: A Reversible Switch Fortifying Cancer Cell Stress-Resilience. THE YALE JOURNAL OF BIOLOGY AND MEDICINE 2025; 98:33-52. [PMID: 40165808 PMCID: PMC11952127 DOI: 10.59249/jkbb6336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Stress adaptation is an evolutionarily conserved mechanism that promotes survival in the face of adverse conditions. AMP-activated protein kinase (AMPK) is a highly conserved energy-sensing kinase found in nearly all eukaryotic cells. It maintains energy homeostasis by promoting catabolism and inhibiting anabolism. In the context of cancer, the role of AMPK is controversial. It was initially touted as a tumor suppressor due to its association with Liver Kinase B1 (LKB1) (an upstream regulator and a known tumor suppressor) and ensuing growth-suppressive actions. However, emerging studies across a variety of cancer types unambiguously reveal AMPK's pro-survival and, thus, tumor-promoting activity, especially under cancer-associated stresses such as hypoxia, nutrient deprivation, oxidative stress, matrix detachment, and chemotherapy. In cancer cells, AMPK is activated in response to stress-induced increases in the levels of adenosine monophosphate (AMP), Ca2+, or reactive oxygen species (ROS). Upon activation, AMPK engages in metabolic rewiring and crosstalk with signaling molecules to mobilize resources toward survival while compromising proliferation. Here, we posit that AMPK is a non-genetic "reversible switch," allowing cancer cells' phenotype to switch to dormant, stem-like, and drug-resistant states, thereby enabling tumor cell survival, pathological progression, and therapy resistance. This review underscores the critical role of AMPK in driving cancer cell stress resilience and survival, advocating for the strategic use of AMPK inhibitors to improve cancer treatment outcomes.
Collapse
Affiliation(s)
- Shraddha S. Mohanty
- Department of Developmental Biology and Genetics, Indian Institute of Science,
Bengaluru, India
| | - Shweta Warrier
- Department of Developmental Biology and Genetics, Indian Institute of Science,
Bengaluru, India
| | - Annapoorni Rangarajan
- Department of Developmental Biology and Genetics, Indian Institute of Science,
Bengaluru, India
| |
Collapse
|
|
3
|
Yuan J, Yang L, Zhang H, Beeraka NM, Zhang D, Wang Q, Wang M, Pr HV, Sethi G, Wang G. Decoding tumor microenvironment: EMT modulation in breast cancer metastasis and therapeutic resistance, and implications of novel immune checkpoint blockers. Biomed Pharmacother 2024; 181:117714. [PMID: 39615165 DOI: 10.1016/j.biopha.2024.117714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 11/15/2024] [Accepted: 11/25/2024] [Indexed: 12/21/2024] Open
Abstract
Tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT) play crucial roles in the initiation and progression of tumors. TME is composed of various cell types, such as immune cells, fibroblasts, and endothelial cells, as well as non-cellular components like extracellular matrix (ECM) proteins and soluble factors. These elements interact with tumor cells through a complex network of signaling pathways involving cytokines, growth factors, metabolites, and non-coding RNA-carrying exosomes. Hypoxic conditions within the TME further modulate these interactions, collectively influencing tumor growth, metastatic potential, and response to therapy. EMT represents a dynamic and reversible process where epithelial cells undergo phenotypic changes to adopt mesenchymal characteristics in several cancers, including breast cancers. This transformation enhances cell motility and imparts stem cell-like properties, which are closely associated with increased metastatic capability and resistance to conventional cancer treatments. Thus, understanding the crosstalk between the TME and EMT is essential for unraveling the underlying mechanisms of breast cancer metastasis and therapeutic resistance. This review uniquely examines the intricate interplay between the tumor TME and epithelial-mesenchymal transition EMT in driving breast cancer metastasis and treatment resistance. It explores the therapeutic potential of targeting the TME-EMT axis, specifically through CD73-TGF-β dual-blockade, to improve outcomes in triple-negative breast cancer. Additionally, it underscores new strategies to enhance immune checkpoint blockade (ICB) responses by modulating EMT, thereby offering innovative insights for more effective cancer treatment.
Collapse
Affiliation(s)
- Jie Yuan
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Li Yang
- Department of Clinical Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Hua Zhang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Narasimha M Beeraka
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow 119991, Russia; Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Chiyyedu, Anantapuramu, Andhra Pradesh 515721, India; Department of Studies in Molecular Biology, Faculty of Science and Technology, University of Mysore, Mysore, Karnataka, 570006, India.
| | - Danfeng Zhang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Qun Wang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Minghua Wang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Hemanth Vikram Pr
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | - Geng Wang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| |
Collapse
|
|
4
|
Smiles WJ, Ovens AJ, Oakhill JS, Kofler B. The metabolic sensor AMPK: Twelve enzymes in one. Mol Metab 2024; 90:102042. [PMID: 39362600 PMCID: PMC11752127 DOI: 10.1016/j.molmet.2024.102042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/12/2024] [Accepted: 09/27/2024] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of energy metabolism. AMPK is sensitive to acute perturbations to cellular energy status and leverages fundamental bioenergetic pathways to maintain cellular homeostasis. AMPK is a heterotrimer comprised of αβγ-subunits that in humans are encoded by seven individual genes (isoforms α1, α2, β1, β2, γ1, γ2 and γ3), permitting formation of at least 12 different complexes with personalised biochemical fingerprints and tissue expression patterns. While the canonical activation mechanisms of AMPK are well-defined, delineation of subtle, as well as substantial, differences in the regulation of heterogenous AMPK complexes remain poorly defined. SCOPE OF REVIEW Here, taking advantage of multidisciplinary findings, we dissect the many aspects of isoform-specific AMPK function and links to health and disease. These include, but are not limited to, allosteric activation by adenine nucleotides and small molecules, co-translational myristoylation and post-translational modifications (particularly phosphorylation), governance of subcellular localisation, and control of transcriptional networks. Finally, we delve into current debate over whether AMPK can form novel protein complexes (e.g., dimers lacking the α-subunit), altogether highlighting opportunities for future and impactful research. MAJOR CONCLUSIONS Baseline activity of α1-AMPK is higher than its α2 counterpart and is more sensitive to synergistic allosteric activation by metabolites and small molecules. α2 complexes however, show a greater response to energy stress (i.e., AMP production) and appear to be better substrates for LKB1 and mTORC1 upstream. These differences may explain to some extent why in certain cancers α1 is a tumour promoter and α2 a suppressor. β1-AMPK activity is toggled by a 'myristoyl-switch' mechanism that likely precedes a series of signalling events culminating in phosphorylation by ULK1 and sensitisation to small molecules or endogenous ligands like fatty acids. β2-AMPK, not entirely beholden to this myristoyl-switch, has a greater propensity to infiltrate the nucleus, which we suspect contributes to its oncogenicity in some cancers. Last, the unique N-terminal extensions of the γ2 and γ3 isoforms are major regulatory domains of AMPK. mTORC1 may directly phosphorylate this region in γ2, although whether this is inhibitory, especially in disease states, is unclear. Conversely, γ3 complexes might be preferentially regulated by mTORC1 in response to physical exercise.
Collapse
Affiliation(s)
- William J Smiles
- Research Program for Receptor Biochemistry and Tumour Metabolism, Department of Paediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria; Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia.
| | - Ashley J Ovens
- Protein Engineering in Immunity & Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia
| | - Jonathan S Oakhill
- Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Melbourne, Australia; Department of Medicine, University of Melbourne, Parkville, Australia
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumour Metabolism, Department of Paediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| |
Collapse
|
|
5
|
Jinadasa AGRG, Akalanka HMK, Wageesha NDA, Ekanayake S. Metformin as a Potential In Vitro Anticancer Modulator of Adenosine Monophosphate Kinase: A Review. Int J Breast Cancer 2024; 2024:1094274. [PMID: 39246697 PMCID: PMC11380709 DOI: 10.1155/2024/1094274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/21/2024] [Accepted: 07/03/2024] [Indexed: 09/10/2024] Open
Abstract
Metformin (MET) is the commonly prescribed hypoglycemic agent used in the treatment of type 2 diabetes mellitus (DM). Pleiotropic effects of MET are emerging as a medication for other diseases including breast cancer (BC). Therefore, a literature review was conducted to investigate whether the anticancer effects of MET are mediated through adenosine monophosphate kinase (AMPK). This review assessed published data focusing on studies where BC cell lines were treated with MET to explore its potential anticancer effects via AMPK on BC cells. The published data reveals that activated AMPK induces anticancer effects primarily by suppressing cell proliferation, induction of apoptosis, and cell cycle arrest, inhibition of metastasis and invasion, alteration of tumor microenvironment, and downregulation of tumorigenesis. In addition, MET was observed to induce AMPK-mediated effects when combined with other drugs. Further studies on assessing the potential use of MET alone or in combination with other drugs would pave the way to design new treatment strategies for BC.
Collapse
Affiliation(s)
- A G R Greshamali Jinadasa
- Department of Basic Sciences Faculty of Allied Health Sciences University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
| | - H M Kasuni Akalanka
- Rural Health Research Institute Charles Sturt University Orange, Orange, NSW 2800, Australia
| | - N D Amal Wageesha
- Department of Biochemistry Faculty of Medicine Sabaragamuwa University of Sri Lanka, PO Box 01, Hidellana, Ratnapura, Sri Lanka
| | - Sagarika Ekanayake
- Department of Biochemistry Faculty of Medical Science University of Sri Jayewardenepura, Gangodawila, Nugegoda, Sri Lanka
| |
Collapse
|
|
6
|
Li WH, Dang Y, Zhang L, Zhou JC, Zhai HY, Yang Z, Ma K, Wang ZZ. METTL3-mediated m 6A methylation of DNMT1 promotes the progression of non-small cell lung cancer by regulating the DNA methylation of FOXO3a. Heliyon 2024; 10:e28618. [PMID: 38586389 PMCID: PMC10998133 DOI: 10.1016/j.heliyon.2024.e28618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 03/21/2024] [Accepted: 03/21/2024] [Indexed: 04/09/2024] Open
Abstract
Background The aim of this study was to investigate the effect of DNA methylation of Fork Head Box O3 (FOXO3a) on the process of epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC). Methods The expressions of FOXO3a, DNA methyltransferase 1 (DNMT1), METTL3, and EMT-related proteins (E-cadherin and N-cadherin) were measured. The influence of 5-Aza-dC and DNMT1 on the methylation level in the promoter region of FOXO3a was examined through the application of methylation-specific PCR (MSP). Chromatin immunoprecipitation (ChIP) was employed to detect binding between DNMT1 and the FOXO3a promoter. Methylated RNA immunoprecipitation (MeRIP) was utilized to evaluate the level of DNMT1 N6-methyladenosine (m6A) methylation. The assessment of cell viability and invasion abilities of A549 cells was performed using Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. NSCLC xenograft mouse models were established by subcutaneously injected treated A549 cells into nude mice. Results The expression levels of DNMT1 and DNA methylation level FOXO3a were found to be significantly increased, whereas FOXO3a expression was considerably decreased in NSCLC cell lines and NSCLC tumor tissues. Both 5-Aza-dC treatment and DNMT1 knockdown resulted in the down-regulation of DNA methylation levels of FOXO3a while simultaneously up-regulating the expression of FOXO3a. A ChIP assay demonstrated that DNMT1 has the ability to bind to the promoter region of FOXO3a. Furthermore, the knockdown of DNMT1 promoted E-cadherin expression, but inhibited expression of N-cadherin, cell viability, and invasion ability. However, the knockdown of FOXO3a hindered the effect of DNMT1 knockdown on EMT, cell viability, and invasion ability of A549 cells. This was evidenced by decreased E-cadherin expression and increased N-cadherin expression, as well as increased cell viability and invasion ability. Increased expression of DNMT1 resulted from m6A methylation of DNMT1, which was mediated by METTL3. Overexpression of DNMT1 decreased of E-cadherin expression while increased N-cadherin expression, cell viability, and invasion ability in METTL3-shRNA treated A549 cells. In xenograft mouse models, DNMT1 knockdown significantly reduced tumor volumes and tumor weight. DNMT1 knockdown upregulated the expression of FOXO3a and E-cadherin, while downregulated N-cadherin expression in vivo. Conclusion METTL3-mediated m6A methylation of DNMT1 up-regulates FOXO3a promoter methylation, thereby promoting the progression of NSCLC.
Collapse
Affiliation(s)
- Wen-Hai Li
- Department of Thoracic Surgery, Xi 'an International Medical Center Hospital, Xi 'an, 710100, China
| | - Yi Dang
- Department of Thoracic Surgery, Xi 'an International Medical Center Hospital, Xi 'an, 710100, China
| | - Liang Zhang
- Department of Thoracic Surgery, Xi 'an International Medical Center Hospital, Xi 'an, 710100, China
| | - Jin-Cai Zhou
- Department of Thoracic Surgery, Xi 'an International Medical Center Hospital, Xi 'an, 710100, China
| | - Heng-Yu Zhai
- Department of Thoracic Surgery, Xi 'an International Medical Center Hospital, Xi 'an, 710100, China
| | - Zhao Yang
- Department of Thoracic Surgery, Xi 'an International Medical Center Hospital, Xi 'an, 710100, China
| | - Kai Ma
- Department of Thoracic Surgery, Xi 'an International Medical Center Hospital, Xi 'an, 710100, China
| | - Zhuang-Zhuang Wang
- Department of Thoracic Surgery, Xi 'an International Medical Center Hospital, Xi 'an, 710100, China
| |
Collapse
|
|
7
|
Mei W, Mei B, Chang J, Liu Y, Zhou Y, Zhu N, Hu M. Role and regulation of FOXO3a: new insights into breast cancer therapy. Front Pharmacol 2024; 15:1346745. [PMID: 38505423 PMCID: PMC10949727 DOI: 10.3389/fphar.2024.1346745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/16/2024] [Indexed: 03/21/2024] Open
Abstract
Breast cancer is the most common malignancy in the world, particularly affecting female cancer patients. Enhancing the therapeutic strategies for breast cancer necessitates identifying molecular drug targets that effectively eliminate tumor cells. One of these prominent targets is the forkhead and O3a class (FOXO3a), a member of the forkhead transcription factor subfamily. FOXO3a plays a pivotal role in various cellular processes, including apoptosis, proliferation, cell cycle regulation, and drug resistance. It acts as a tumor suppressor in multiple cancer types, although its specific role in cancer remains unclear. Moreover, FOXO3a shows promise as a potential marker for tumor diagnosis and prognosis in breast cancer patients. In addition, it is actively influenced by common anti-breast cancer drugs like paclitaxel, simvastatin, and gefitinib. In breast cancer, the regulation of FOXO3a involves intricate networks, encompassing post-translational modification post-translational regulation by non-coding RNA (ncRNA) and protein-protein interaction. The specific mechanism of FOXO3a in breast cancer urgently requires further investigation. This review aims to systematically elucidate the role of FOXO3a in breast cancer. Additionally, it reviews the interaction of FOXO3a and its upstream and downstream signaling pathway-related molecules to uncover potential therapeutic drugs and related regulatory factors for breast cancer treatment by regulating FOXO3a.
Collapse
Affiliation(s)
- Wenqiu Mei
- Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
- Department of Neurology, Ezhou Central Hospital, Ezhou, China
| | - Bingyin Mei
- Department of Neurology, Ezhou Central Hospital, Ezhou, China
| | - Jing Chang
- Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Yifei Liu
- School of Biomedical Engineering, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Yanhong Zhou
- Department of Medical School of Facial Features, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Ni Zhu
- Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Meichun Hu
- Key Laboratory of Environmental Related Diseases and One Health, School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| |
Collapse
|
|
8
|
Ouyang Y, Gu Y, Zhang X, Huang Y, Wei X, Tang F, Zhang S. AMPKα2 promotes tumor immune escape by inducing CD8+ T-cell exhaustion and CD4+ Treg cell formation in liver hepatocellular carcinoma. BMC Cancer 2024; 24:276. [PMID: 38424484 PMCID: PMC10905944 DOI: 10.1186/s12885-024-12025-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 02/20/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Adenosine monophosphate-activated protein kinase (AMPK) is associated with the development of liver hepatocellular carcinoma (LIHC). AMPKα2, an α2 subunit of AMPK, is encoded by PRKAA2, and functions as the catalytic core of AMPK. However, the role of AMPKα2 in the LIHC tumor immune environment is unclear. METHODS RNA-seq data were obtained from the Cancer Genome Atlas and Genotype-Tissue Expression databases. Using the single-cell RNA-sequencing dataset for LIHC obtained from the China National Genebank Database, the communication between malignant cells and T cells in response to different PRKAA2 expression patterns was evaluated. In addition, the association between PRKAA2 expression and T-cell evolution during tumor progression was explored using Pseudotime analysis, and the role of PRKAA2 in metabolic reprogramming was explored using the R "scMetabolis" package. Functional experiments were performed in LIHC HepG2 cells. RESULTS AMPK subunits were expressed in tissue-specific and substrate-specific patterns. PRKAA2 was highly expressed in LIHC tissues and was associated with poor patient prognosis. Tumors with high PRKAA2 expression displayed an immune cold phenotype. High PRKAA2 expression significantly promoted LIHC immune escape. This result is supported by the following evidence: 1) the inhibition of major histocompatibility complex class I (MHC-I) expression through the regulation of interferon-gamma activity in malignant cells; 2) the promotion of CD8+ T-cell exhaustion and the formation of CD4+ Treg cells in T cells; 3) altered interactions between malignant cells and T cells in the tumor immune environment; and 4) induction of metabolic reprogramming in malignant cells. CONCLUSIONS Our study indicate that PRKAA2 may contribute to LIHC progression by promoting metabolic reprogramming and tumor immune escape through theoretical analysis, which offers a theoretical foundation for developing PRKAA2-based strategies for personalized LIHC treatment.
Collapse
Affiliation(s)
- Yan Ouyang
- Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Guizhou Medical University, Guiyang, China
| | - Yan Gu
- Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Guizhou Medical University, Guiyang, China
| | - Xinhai Zhang
- Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Guizhou Medical University, Guiyang, China
| | - Ya Huang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, China
| | - Xianpeng Wei
- Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Guizhou Medical University, Guiyang, China
| | - Fuzhou Tang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, China.
| | - Shichao Zhang
- Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, China.
| |
Collapse
|
|
9
|
Asanoma K, Yagi H, Onoyama I, Cui L, Hori E, Kawakami M, Maenohara S, Hachisuga K, Tomonobe H, Kodama K, Yasunaga M, Ohgami T, Okugawa K, Yahata H, Kitao H, Kato K. The BHLHE40‒PPM1F‒AMPK pathway regulates energy metabolism and is associated with the aggressiveness of endometrial cancer. J Biol Chem 2024; 300:105695. [PMID: 38301894 PMCID: PMC10904277 DOI: 10.1016/j.jbc.2024.105695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 01/03/2024] [Accepted: 01/17/2024] [Indexed: 02/03/2024] Open
Abstract
BHLHE40 is a basic helix-loop-helix transcription factor that is involved in multiple cell activities including differentiation, cell cycle, and epithelial-to-mesenchymal transition. While there is growing evidence to support the functions of BHLHE40 in energy metabolism, little is known about the mechanism. In this study, we found that BHLHE40 expression was downregulated in cases of endometrial cancer of higher grade and advanced disease. Knockdown of BHLHE40 in endometrial cancer cells resulted in suppressed oxygen consumption and enhanced extracellular acidification. Suppressed pyruvate dehydrogenase (PDH) activity and enhanced lactated dehydrogenase (LDH) activity were observed in the knockdown cells. Knockdown of BHLHE40 also led to dephosphorylation of AMPKα Thr172 and enhanced phosphorylation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) Ser293 and lactate dehydrogenase A (LDHA) Tyr10. These results suggested that BHLHE40 modulates PDH and LDH activity by regulating the phosphorylation status of PDHA1 and LDHA. We found that BHLHE40 enhanced AMPKα phosphorylation by directly suppressing the transcription of an AMPKα-specific phosphatase, PPM1F. Our immunohistochemical study showed that the expression of BHLHE40, PPM1F, and phosphorylated AMPKα correlated with the prognosis of endometrial cancer patients. Because AMPK is a central regulator of energy metabolism in cancer cells, targeting the BHLHE40‒PPM1F‒AMPK axis may represent a strategy to control cancer development.
Collapse
Affiliation(s)
- Kazuo Asanoma
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Hiroshi Yagi
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ichiro Onoyama
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Lin Cui
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Emiko Hori
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Minoru Kawakami
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shoji Maenohara
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuhisa Hachisuga
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroshi Tomonobe
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keisuke Kodama
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Yasunaga
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tatsuhiro Ohgami
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kaoru Okugawa
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideaki Yahata
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroyuki Kitao
- Oral Medicine Research Center, Fukuoka Dental College, Fukuoka, Japan
| | - Kiyoko Kato
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| |
Collapse
|
|
10
|
Zhang Y, Yang F, Wu J, Huang J, Li P, Huang G. Idebenone Exerts anti-Triple Negative Breast Cancer Effects via Dual Signaling Pathways of GADD45 and AMPK. Nutr Cancer 2024; 76:379-392. [PMID: 38332562 DOI: 10.1080/01635581.2024.2314320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 01/28/2024] [Accepted: 01/30/2024] [Indexed: 02/10/2024]
Abstract
Idebenone, a mitochondrial regulator, has exhibited anti-cancer activity in neurogenic and prostate tumor cells; however, its efficacy and specific targets in the treatment of triple-negative breast cancer (TNBC) remain unclear. This study aims to evaluate the potential of Idebenone as a therapeutic agent for TNBC. TNBC cell lines and Xenograft mouse models were used to assess the effect of Idebenone on TNBC both in vitro and in vivo. To investigate the underlying mechanism of Idebenone's effect on TNBC, cell viability assay, transwell invasion assay, cell cycle analysis, apoptosis assay, mitochondrial membrane potential assay, immunofluorescence staining, and transcriptome sequencing were utilized. The results showed that Idebenone impeded the proliferation, colony formation, migration, and invasion of TNBC cells, suppressed apoptosis, and halted the cell cycle in the G2/M phase. The inhibitory effect of Idebenone on TNBC was associated with the GADD45/CyclinB/CDK1 signaling pathway. By disrupting the mitochondrial membrane potential (MMP) and promoting mitophagy, Idebenone promoted cell autophagy through the AMPK/mTOR pathway, thus further suppressing the proliferation of TNBC cells. Furthermore, we found that Idebenone inhibited the development of TNBC in vivo. In conclusion, Idebenone may be a promising therapeutic option for TNBC as it is capable of inducing autophagy and apoptosis.
Collapse
Affiliation(s)
- Yidan Zhang
- Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Fan Yang
- Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiahao Wu
- Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jianhong Huang
- Department of General Surgery, Zengcheng District Hospital of Traditional Chinese Medicine, China
| | - Peiqing Li
- Department of General Surgery, Xinyi People's Hospital, Xinyi, China
| | - Guanqun Huang
- Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of General Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| |
Collapse
|
|
11
|
Zheng B, Du P, Zeng Z, Cao P, Ma X, Jiang Y. Propranolol inhibits EMT and metastasis in breast cancer through miR-499-5p-mediated Sox6. J Cancer Res Clin Oncol 2024; 150:59. [PMID: 38294713 PMCID: PMC10830604 DOI: 10.1007/s00432-023-05599-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 12/25/2023] [Indexed: 02/01/2024]
Abstract
PURPOSE This study will focus on 4T1 cells, a murine mammary adenocarcinoma cell line, as the primary research subject. We aim to investigate the inhibitory effects and mechanisms of propranolol on epithelial-mesenchymal transition (EMT) in breast cancer cells, aiming to elucidate this phenomenon at the miRNA level. METHODS In this study, the EMT inhibitory effect of propranolol was observed through in vitro and animal experiments. For the screening of potential target miRNAs and downstream target genes, second-generation sequencing (SGS) and bioinformatics analysis were conducted. Following the screening process, the identified target miRNAs and their respective target genes were confirmed using various experimental methods. To confirm the target miRNAs and target genes, Western Blot (WB), reverse transcription polymerase chain reaction (RT-PCR), and immunofluorescence experiments were performed. RESULTS In this study, we found that propranolol significantly reduced lung metastasis in 4T1 murine breast cancer cells (p < 0.05). In vitro and in vivo experiments demonstrated that propranolol inhibited the epithelial-mesenchymal transition (EMT) as evidenced by Western Blot analysis (p < 0.05). Through next-generation sequencing (SGS), subsequent bioinformatics analysis, and PCR validation, we identified a marked downregulation of miR-499-5p (p < 0.05), suggesting its potential involvement in mediating the suppressive effects of propranolol on EMT. Overexpression of miR-499-5p promoted EMT, migration, and invasion of 4T1 cells, and these effects were not reversed or attenuated by propranolol (Validated via Western Blot, wound healing assay, transwell migration, and invasion assays, p < 0.05). Sox6 was identified as a functional target of miR-499-5p, with its downregulation correlating with the observed EMT changes (p < 0.05). Silencing Sox6 or overexpressing miR-499-5p inhibited Sox6 expression, further promoting the processes of EMT, invasion, and migration in 4T1 cells. Notably, these effects were not alleviated by propranolol (validated via Western Blot, wound healing assay, transwell migration, and invasion assays, p < 0.05). The direct interaction between miR-499-5p and Sox6 mRNA was confirmed by dual-luciferase reporter gene assay. CONCLUSION These results suggest that propranolol may have potential as a therapeutic agent for breast cancer treatment by targeting EMT and its regulatory mechanisms.
Collapse
Affiliation(s)
- Bo Zheng
- Health Management Center, Department of Oncology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - PeiXin Du
- Institute for Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Zhi Zeng
- Huaxi Clinical College, Sichuan University, Chengdu, 610041, China
| | - Peng Cao
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
| | - Yu Jiang
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan, 610041, China.
| |
Collapse
|
|
12
|
Bui KC, Nguyen TML, Barat S, Scholta T, Xing J, Bhuria V, Sipos B, Wilkens L, Nguyen LT, Le HS, Velavan TP, Bozko P, Plentz RR. Novel Adiponectin Receptor Agonist Inhibits Cholangiocarcinoma via Adenosine Monophosphate-activated Protein Kinase. Curr Med Chem 2024; 31:4534-4548. [PMID: 38361349 DOI: 10.2174/0109298673254969231122114107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 10/06/2023] [Accepted: 10/26/2023] [Indexed: 02/17/2024]
Abstract
BACKGROUND Cholangiocarcinoma (CCA) has a poor prognosis and only limited palliative treatment options. The deficiency of adiponectin and adenosine monophosphate-activated protein kinase (AMPK) signaling was reported in several malignancies, but the alteration of these proteins in CCA is still unclear. OBJECTIVES This study aimed to assess the role of adiponectin and AMPK signaling in CCA. Furthermore, AdipoRon, a novel adiponectin receptor (AdipoR) agonist, was evaluated in vitro and in vivo as a new anti-tumor therapy for CCA. METHODS The expression of AdipoR1 and p-AMPKα in human tissue microarrays (TMAs) was evaluated by immunohistochemistry staining (IHC). The effect of 2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-4-piperidinyl]-acetamide (AdipoRon) was investigated in vitro with proliferation, crystal violet, migration, invasion, colony formation, senescence, cell cycle and apoptosis assays and in vivo using a CCA engineered mouse model (AlbCre/LSL-KRASG12D/p53L/L). RT-qPCR and western blot methods were applied to study molecular alterations in murine tissues. RESULTS AdipoR1 and p-AMPKα were impaired in human CCA tissues, compared to adjacent non-tumor tissue. There was a positive correlation between the AdipoR1 and p-AMPKα levels in CCA tissues. Treatment with AdipoRon inhibited proliferation, migration, invasion and colony formation and induced apoptosis in a time- and dose-dependent manner in vitro (p<0.05). In addition, AdipoRon reduced the number of CCA and tumor volume, prolonged survival, and decreased metastasis and ascites in the treated group compared to the control group (p<0.05). CONCLUSIONS AdipoR1 and p-AMPKα are impaired in CCA tissues, and AdipoRon effectively inhibits CCA in vitro and in vivo. Thus, AdipoRon may be considered as a potential anti-tumor therapy in CCA.
Collapse
Affiliation(s)
- Khac Cuong Bui
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
- Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
- Laboratory Animal Research Center, Vietnam Military Medical University, Hanoi, Vietnam
- Vietnamese-German Centre for Medical Research (VG-CARE), Hanoi, Vietnam
| | - Thi Mai Ly Nguyen
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
- Vietnamese-German Centre for Medical Research (VG-CARE), Hanoi, Vietnam
- Department of Biochemistry, Military Hospital 103, Vietnam Military Medical University, Hanoi, Vietnam
| | - Samarpita Barat
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Tim Scholta
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Jun Xing
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Vikas Bhuria
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Health-Campus Immunology, Infectiology, and Inflammation, Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
- Center for Health and Medical Prevention-ChaMP, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Bence Sipos
- Department of Internal Medicine VIII, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Ludwig Wilkens
- Institute of Pathology, Nordstadt Krankenhaus, Hannover, Germany
| | - Linh Toan Nguyen
- Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
| | - Huu Song Le
- Vietnamese-German Centre for Medical Research (VG-CARE), Hanoi, Vietnam
- Faculty of Tropical and Infectious Diseases, 108 Military Central Hospital, Hanoi, Vietnam
| | - Thirumalaisamy P Velavan
- Vietnamese-German Centre for Medical Research (VG-CARE), Hanoi, Vietnam
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Tübingen, Germany
- Duy Tan University, Da Nang, Vietnam
| | - Przemyslaw Bozko
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Ruben R Plentz
- Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany
- Department of Internal Medicine, Klinikum Bremen Nord, Bremen, Germany
| |
Collapse
|
|
13
|
Tang Z, Zhang Y, Yu Z, Luo Z. Metformin Suppresses Stemness of Non-Small-Cell Lung Cancer Induced by Paclitaxel through FOXO3a. Int J Mol Sci 2023; 24:16611. [PMID: 38068934 PMCID: PMC10705988 DOI: 10.3390/ijms242316611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 12/18/2023] Open
Abstract
Cancer stem cells (CSCs) play a pivotal role in drug resistance and metastasis. Among the key players, Forkhead box O3a (FOXO3a) acts as a tumor suppressor. This study aimed to unravel the role of FOXO3a in mediating the inhibitory effect of metformin on cancer stemness derived from paclitaxel (PTX)-resistant non-small-cell lung cancer (NSCLC) cells. We showed that CSC-like features were acquired by the chronic induction of resistance to PTX, concurrently with inactivation of FOXO3a. In line with this, knockdown of FOXO3a in PTX-sensitive cells led to changes toward stemness, while overexpression of FOXO3a in PTX-resistant cells mitigated stemness in vitro and remarkably curbed the tumorigenesis of NSCLC/PTX cells in vivo. Furthermore, metformin suppressed the self-renewal ability of PTX-resistant cells, reduced the expression of stemness-related markers (c-MYC, Oct4, Nanog and Notch), and upregulated FOXO3a, events concomitant with the activation of AMP-activated protein kinase (AMPK). All these changes were recapitulated by silencing FOXO3a in PTX-sensitive cells. Intriguingly, the introduction of the AMPK dominant negative mutant offset the inhibitory effect of metformin on the stemness of PTX-resistant cells. In addition, FOXO3a levels were elevated by the treatment of PTX-resistant cells with MK2206 (an Akt inhibitor) and U0126 (a MEK inhibitor). Collectively, our findings indicate that metformin exerts its effect on FOXO3a through the activation of AMPK and the inhibition of protein kinase B (Akt) and MAPK/extracellular signal-regulated kinase (MEK), culminating in the suppression of stemness in paclitaxel-resistant NSCLC cells.
Collapse
Affiliation(s)
- Zhimin Tang
- Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China;
| | - Yilan Zhang
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
| | - Zhengyi Yu
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
| | - Zhijun Luo
- Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China;
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330031, China; (Y.Z.); (Z.Y.)
| |
Collapse
|
|
14
|
Jiang S, Han X, Zhao Z, Song D, Cheng S, Liu T, Zhao X, Gu Y, Duan L, Gao S. Hypoxia inhibits HUNK kinase activity to induce epithelial-mesenchymal transition. Biochem Biophys Res Commun 2023; 681:271-275. [PMID: 37793312 DOI: 10.1016/j.bbrc.2023.09.074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 09/24/2023] [Accepted: 09/25/2023] [Indexed: 10/06/2023]
Abstract
Hypoxia is a common hallmark of cancer and plays a crucial role in promoting epithelial-mesenchymal transition (EMT). Hormonally Upregulated Neu-associated Kinase (HUNK) regulates EMT through its kinase activity. However, whether hypoxia is involved in HUNK-mediated EMT is incompletely understood. This study unveils an association between HUNK kinase activity and hypoxia in colorectal cancer (CRC). Importantly, hypoxia does not alter the expression levels of HUNK, but directly affects the phosphorylation levels of downstream proteins with indication of HUNK activity. Functionally, the upregulation of migration, invasion, and expression of EMT markers in CRC cells under hypoxic conditions can be attributed, in part, to the downregulation of HUNK-mediated phosphorylation of downstream proteins. These findings highlight the intricate relationship between HUNK, hypoxia and the molecular mechanisms of cancer EMT. Understanding these mechanisms may provide valuable insights into therapeutic targets for inhibiting cancer metastasis.
Collapse
Affiliation(s)
- Siyuan Jiang
- Zhongda Hospital, Medical School, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
| | - Xiaoqi Han
- Shanxi Academy of Advanced Research and Innovation, Taiyuan, 030032, China; Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
| | - Zidong Zhao
- Zhongda Hospital, Medical School, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
| | - Dalong Song
- The People's Hospital of Guizhou Province, Guiyang, 550002, China
| | - Shuwen Cheng
- Nanjing University Medical School, Nanjing, 210046, China
| | - Tihui Liu
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
| | - Xujie Zhao
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
| | - Yinmin Gu
- Zhongda Hospital, Medical School, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China
| | - Liqiang Duan
- Shanxi Academy of Advanced Research and Innovation, Taiyuan, 030032, China
| | - Shan Gao
- Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, 210096, China.
| |
Collapse
|
|
15
|
Moutabian H, Radi UK, Saleman AY, Adil M, Zabibah RS, Chaitanya MNL, Saadh MJ, Jawad MJ, Hazrati E, Bagheri H, Pal RS, Akhavan-Sigari R. MicroRNA-155 and cancer metastasis: Regulation of invasion, migration, and epithelial-to-mesenchymal transition. Pathol Res Pract 2023; 250:154789. [PMID: 37741138 DOI: 10.1016/j.prp.2023.154789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/24/2023] [Accepted: 09/01/2023] [Indexed: 09/25/2023]
Abstract
Among the leading causes of death globally has been cancer. Nearly 90% of all cancer-related fatalities are attributed to metastasis, which is the growing of additional malignant growths out of the original cancer origin. Therefore, a significant clinical need for a deeper comprehension of metastasis exists. Beginning investigations are being made on the function of microRNAs (miRNAs) in the metastatic process. Tiny non-coding RNAs called miRNAs have a crucial part in controlling the spread of cancer. Some miRNAs regulate migration, invasion, colonization, cancer stem cells' properties, the epithelial-mesenchymal transition (EMT), and the microenvironment, among other processes, to either promote or prevent metastasis. One of the most well-conserved and versatile miRNAs, miR-155 is primarily distinguished by overexpression in a variety of illnesses, including malignant tumors. It has been discovered that altered miR-155 expression is connected to a number of physiological and pathological processes, including metastasis. As a result, miR-155-mediated signaling pathways were identified as possible cancer molecular therapy targets. The current research on miR-155, which is important in controlling cancer cells' invasion, and metastasis as well as migration, will be summarized in the current work. The crucial significance of the lncRNA/circRNA-miR-155-mRNA network as a crucial regulator of carcinogenesis and a player in the regulation of signaling pathways or related genes implicated in cancer metastasis will be covered in the final section. These might provide light on the creation of fresh treatment plans for controlling cancer metastasis.
Collapse
Affiliation(s)
- Hossein Moutabian
- Radiation Sciences Research Center (RSRC), AJA University of Medical Sciences, Tehran, Iran
| | - Usama Kadem Radi
- College of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | | | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Mv N L Chaitanya
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144402, India
| | - Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan; Applied Science Research Center. Applied Science Private University, Amman, Jordan
| | | | - Ebrahi Hazrati
- Trauma Research Center, AJA University of Medical Sciences, Tehran, Iran
| | - Hamed Bagheri
- Radiation Sciences Research Center (RSRC), AJA University of Medical Sciences, Tehran, Iran; Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Rashmi Saxena Pal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144402, India
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center, Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
| |
Collapse
|
|
16
|
Saha A, Kolonin MG, DiGiovanni J. Obesity and prostate cancer - microenvironmental roles of adipose tissue. Nat Rev Urol 2023; 20:579-596. [PMID: 37198266 DOI: 10.1038/s41585-023-00764-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2023] [Indexed: 05/19/2023]
Abstract
Obesity is known to have important roles in driving prostate cancer aggressiveness and increased mortality. Multiple mechanisms have been postulated for these clinical observations, including effects of diet and lifestyle, systemic changes in energy balance and hormonal regulation and activation of signalling by growth factors and cytokines and other components of the immune system. Over the past decade, research on obesity has shifted towards investigating the role of peri-prostatic white adipose tissue as an important source of locally produced factors that stimulate prostate cancer progression. Cells that comprise white adipose tissue, the adipocytes and their progenitor adipose stromal cells (ASCs), which proliferate to accommodate white adipose tissue expansion in obesity, have been identified as important drivers of obesity-associated cancer progression. Accumulating evidence suggests that adipocytes are a source of lipids that are used by adjacent prostate cancer cells. However, results of preclinical studies indicate that ASCs promote tumour growth by remodelling extracellular matrix and supporting neovascularization, contributing to the recruitment of immunosuppressive cells, and inducing epithelial-mesenchymal transition through paracrine signalling. Because epithelial-mesenchymal transition is associated with cancer chemotherapy resistance and metastasis, ASCs are considered to be potential targets of therapies that could be developed to suppress cancer aggressiveness in patients with obesity.
Collapse
Affiliation(s)
- Achinto Saha
- Division of Pharmacology and Toxicology and Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX, USA
- Center for Molecular Carcinogenesis and Toxicology, The University of Texas at Austin, Austin, TX, USA
- Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
| | - Mikhail G Kolonin
- The Brown Foundation Institute of Molecular Medicine for the Prevention of Disease, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
| | - John DiGiovanni
- Division of Pharmacology and Toxicology and Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX, USA.
- Center for Molecular Carcinogenesis and Toxicology, The University of Texas at Austin, Austin, TX, USA.
- Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
| |
Collapse
|
|
17
|
Razi S, Mozdarani H, Behzadi Andouhjerdi R. Evaluation of the Potential Diagnostic Role of the Lnc-MIAT, miR-29a-3p, and FOXO3a ceRNA Networks as Noninvasive Circulatory Bioindicator in Ductal Carcinoma Breast Cancer. Breast Cancer (Auckl) 2023; 17:11782234231184378. [PMID: 37434996 PMCID: PMC10331106 DOI: 10.1177/11782234231184378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 06/06/2023] [Indexed: 07/13/2023] Open
Abstract
Background Over the last few decades, tremendous progress has been achieved in the early detection and treatment of breast cancer (BC). However, the prognosis remains unsatisfactory, and the underlying processes of carcinogenesis are still unclear. The purpose of this research was to find out the relationship between myocardial infarction-associated transcript (MIAT), FOXO3a, and miRNA29a-3p and evaluated the expression levels in patients compare with control and their potential as a noninvasive bioindicator in whole blood in BC. Methods Whole blood and BC tissue are taken from patients before radiotherapy and chemotherapy. Total RNA was extracted from BC tissue and whole blood to synthesize complementary DNA (cDNA). The expression of MIAT, FOXO3a, and miRNA29a-3p was analyzed by the quantitative reverse transcription-polymerase chain reaction (RT-qPCR) method and the sensitivity and specificity of them were determined by the receiver operating characteristic (ROC) curve. Bioinformatics analysis was used to understand the connections between MIAT, FOXO3a, and miRNA29a-3p in human BC to develop a ceRNA (competitive endogenous RNA) network. Results We identified that in ductal carcinoma BC tissue and whole blood, MIAT and FOXO3a were more highly expressed, whereas miRNA29a-3p was lower compared with those in nontumor samples. There was a positive correlation between the expression levels of MIAT, FOXO3a, and miRNA29a-3p in BC tissues and whole blood. Our results also proposed miRNA29a-3p as a common target between MIAT and FOXO3a, and we showed them as a ceRNA network. Conclusions This is the first study that indicates MIAT, FOXO3a, and miRNA29a-3p as a ceRNA network, and their expression was analyzed in both BC tissue and whole blood. As a preliminary assessment, our findings indicate that combined levels of MIAT, FOXO3a, and miR29a-3p may be considered as potential diagnostic bioindicator for BC.
Collapse
Affiliation(s)
- Shokufeh Razi
- Department of Genetics, Faculty of
Basic Sciences, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Hossein Mozdarani
- Department of Medical Genetics, Faculty
of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | |
Collapse
|
|
18
|
Kuduvalli SS, Daisy PS, Vaithy A, Purushothaman M, Ramachandran Muralidharan A, Agiesh KB, Mezger M, Antony JS, Subramani M, Dubashi B, Biswas I, Guruprasad KP, Anitha TS. A combination of metformin and epigallocatechin gallate potentiates glioma chemotherapy in vivo. Front Pharmacol 2023; 14:1096614. [PMID: 37025487 PMCID: PMC10070706 DOI: 10.3389/fphar.2023.1096614] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 03/02/2023] [Indexed: 04/08/2023] Open
Abstract
Glioma is the most devastating high-grade tumor of the central nervous system, with dismal prognosis. Existing treatment modality does not provide substantial benefit to patients and demands novel strategies. One of the first-line treatments for glioma, temozolomide, provides marginal benefit to glioma patients. Repurposing of existing non-cancer drugs to treat oncology patients is gaining momentum in recent years. In this study, we investigated the therapeutic benefits of combining three repurposed drugs, namely, metformin (anti-diabetic) and epigallocatechin gallate (green tea-derived antioxidant) together with temozolomide in a glioma-induced xenograft rat model. Our triple-drug combination therapy significantly inhibited tumor growth in vivo and increased the survival rate (50%) of rats when compared with individual or dual treatments. Molecular and cellular analyses revealed that our triple-drug cocktail treatment inhibited glioma tumor growth in rat model through ROS-mediated inactivation of PI3K/AKT/mTOR pathway, arrest of the cell cycle at G1 phase and induction of molecular mechanisms of caspases-dependent apoptosis.In addition, the docking analysis and quantum mechanics studies performed here hypothesize that the effect of triple-drug combination could have been attributed by their difference in molecular interactions, that maybe due to varying electrostatic potential. Thus, repurposing metformin and epigallocatechin gallate and concurrent administration with temozolomide would serve as a prospective therapy in glioma patients.
Collapse
Affiliation(s)
- Shreyas S. Kuduvalli
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | - Precilla S. Daisy
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | - Anandraj Vaithy
- Department of Pathology, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | | | - Arumugam Ramachandran Muralidharan
- Department of Visual Neurosciences, Singapore Eye Research Institute, Singapore, Singapore
- Eye-APC, Duke-NUS Medical School, Singapore, Singapore
| | - Kumar B. Agiesh
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | - Markus Mezger
- University Children’s Hospital Tübingen, Department of General Paediatrics, Haematology /Oncology, Tübingen, Germany
| | - Justin S. Antony
- University Children’s Hospital Tübingen, Department of General Paediatrics, Haematology /Oncology, Tübingen, Germany
| | | | - Biswajit Dubashi
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Indrani Biswas
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | - K. P. Guruprasad
- Department of Ageing Research, Manipal School of Life Sciences, MAHE, Manipal, Karnataka, India
| | - T. S. Anitha
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| |
Collapse
|
|
19
|
Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy. Cell Mol Immunol 2023; 20:318-340. [PMID: 36823234 PMCID: PMC10066239 DOI: 10.1038/s41423-023-00980-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/17/2023] [Indexed: 02/25/2023] Open
Abstract
Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, most patients fail to respond or achieve durable responses due to primary or acquired ICB resistance. Recently, tumor epithelial-to-mesenchymal plasticity (EMP) was identified as a critical determinant in regulating immune escape and immunotherapy resistance in cancer. In this review, we summarize the emerging role of tumor EMP in ICB resistance and the tumor-intrinsic or extrinsic mechanisms by which tumors exploit EMP to achieve immunosuppression and immune escape. We discuss strategies to modulate tumor EMP to alleviate immune resistance and to enhance the efficiency of ICB therapy. Our discussion provides new prospects to enhance the ICB response for therapeutic gain in cancer patients.
Collapse
|
|
20
|
Konieczny P, Adamus T, Sułkowski M, Skrzypek K, Majka M. Impact of AMPK on cervical carcinoma progression and metastasis. Cell Death Dis 2023; 14:43. [PMID: 36658117 PMCID: PMC9852279 DOI: 10.1038/s41419-023-05583-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 01/05/2023] [Accepted: 01/11/2023] [Indexed: 01/20/2023]
Abstract
Cervical cancer (CC) is the fourth most common malignant neoplasm among women. Late diagnosis is directly associated with the incidence of metastatic disease and remarkably limits the effectiveness of conventional anticancer therapies at the advanced tumor stage. In this study, we investigated the role of 5'AMP-activated kinase (AMPK) in the metastatic progression of cervical cancer. Since the epithelial mesenchymal transition (EMT) is known as major mechanism enabling cancer cell metastasis, cell lines, which accurately represent this process, have been used as a research model. We used C-4I and HTB-35 cervical cancer cell lines representing distant stages of the disease, in which we genetically modified the expression of the AMPK catalytic subunit α. We have shown that tumor progression leads to metabolic deregulation which results in reduced expression and activity of AMPK. We also demonstrated that AMPK is related to the ability of cells to acquire invasive phenotype and potential for in vivo metastases, and its activity may inhibit these processes. Our findings support the hypothesis that AMPK is a promising therapeutic target and modulation of its expression and activity may improve the efficacy of cervical cancer treatment.
Collapse
Affiliation(s)
- Paweł Konieczny
- Jagiellonian University Medical College, Faculty of Medicine, Institute of Pediatrics, Department of Transplantation, Krakow, Poland
| | - Tomasz Adamus
- Jagiellonian University Medical College, Faculty of Medicine, Institute of Pediatrics, Department of Transplantation, Krakow, Poland
| | - Maciej Sułkowski
- Jagiellonian University Medical College, Faculty of Medicine, Institute of Pediatrics, Department of Transplantation, Krakow, Poland
| | - Klaudia Skrzypek
- Jagiellonian University Medical College, Faculty of Medicine, Institute of Pediatrics, Department of Transplantation, Krakow, Poland
| | - Marcin Majka
- Jagiellonian University Medical College, Faculty of Medicine, Institute of Pediatrics, Department of Transplantation, Krakow, Poland.
| |
Collapse
|
|
21
|
Wang NF, Jue TR, Holst J, Gunter JH. Systematic review of antitumour efficacy and mechanism of metformin activity in prostate cancer models. BJUI COMPASS 2023; 4:44-58. [PMID: 36569495 PMCID: PMC9766874 DOI: 10.1002/bco2.187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/07/2022] [Accepted: 08/08/2022] [Indexed: 12/27/2022] Open
Abstract
Metformin, the first line pharmacotherapy for type 2 diabetes has demonstrated favourable effects in prostate cancer (PCa) across a range of studies evaluating PCa patient outcomes amongst metformin users. However, a lack of rigorously conducted prospective studies has stalled clinical use in this setting. Despite multiple studies evaluating the mechanisms underpinning antitumour effects of metformin in PCa, to date, no reviews have compared these findings. This systematic review and meta-analysis consolidates the mechanisms accounting for the antitumour effect of metformin in PCa and evaluates the antitumour efficacy of metformin in preclinical PCa studies. Data were obtained through Medline and EMBASE, extracted by two independent assessors. Risk of bias was assessed using the TOXR tool. Meta-analysis compared in vivo reductions of PCa tumour volume with metformin. In total, 447 articles were identified with 80 duplicates, and 261 articles excluded based on eligibility criteria. The remaining 106 articles were assessed and 71 excluded, with 35 articles included for systematic review, and eight included for meta-analysis. The mechanisms of action of metformin regarding tumour growth, viability, migration, invasion, cell metabolism, and activation of signalling cascades are individually discussed. The mechanisms by which metformin inhibits PCa cell growth are multimodal. Metformin regulates expression of multiple proteins/genes to inhibit cellular proliferation, cell cycle progression, and cellular invasion and migration. Published in vivo studies also conclusively demonstrate that metformin inhibits PCa growth. This highlights the potential of metformin to be repurposed as an anticancer agent, warranting further investigation of metformin in the setting of PCa.
Collapse
Affiliation(s)
- Nan Fang Wang
- School of Medical SciencesUNSW SydneySydneyNSWAustralia
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Toni Rose Jue
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Jeff Holst
- School of Medical SciencesUNSW SydneySydneyNSWAustralia
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Jennifer H. Gunter
- Australian Prostate Cancer Research Centre‐Queensland, Centre for Genomic and Personalised Health, School of Biomedical Sciences, Faculty of Health, Translational Research InstituteQueensland University of Technology (QUT)BrisbaneQLDAustralia
| |
Collapse
|
|
22
|
Galbraith M, Levine H, Onuchic JN, Jia D. Decoding the coupled decision-making of the epithelial-mesenchymal transition and metabolic reprogramming in cancer. iScience 2022; 26:105719. [PMID: 36582834 PMCID: PMC9792913 DOI: 10.1016/j.isci.2022.105719] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/03/2022] [Accepted: 11/30/2022] [Indexed: 12/11/2022] Open
Abstract
Cancer metastasis relies on an orchestration of traits driven by different interacting functional modules, including metabolism and epithelial-mesenchymal transition (EMT). During metastasis, cancer cells can acquire a hybrid metabolic phenotype (W/O) by increasing oxidative phosphorylation without compromising glycolysis and they can acquire a hybrid epithelial/mesenchymal (E/M) phenotype by engaging EMT. Both the W/O and E/M states are associated with high metastatic potentials, and many regulatory links coupling metabolism and EMT have been identified. Here, we investigate the coupled decision-making networks of metabolism and EMT. Their crosstalk can exhibit synergistic or antagonistic effects on the acquisition and stability of different coupled metabolism-EMT states. Strikingly, the aggressive E/M-W/O state can be enabled and stabilized by the crosstalk irrespective of these hybrid states' availability in individual metabolism or EMT modules. Our work emphasizes the mutual activation between metabolism and EMT, providing an important step toward understanding the multifaceted nature of cancer metastasis.
Collapse
Affiliation(s)
- Madeline Galbraith
- Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA,Department of Physics and Astronomy, Rice University, Houston, TX77005, USA
| | - Herbert Levine
- Center for Theoretical Biological Physics, Department of Physics, and Department of Bioengineering, Northeastern University, Boston, MA02115, USA,Corresponding author
| | - José N. Onuchic
- Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA,Department of Physics and Astronomy, Rice University, Houston, TX77005, USA,Department of Chemistry, Rice University, Houston, TX77005, USA,Department of Biosciences, Rice University, Houston, TX77005, USA,Corresponding author
| | - Dongya Jia
- Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA,Corresponding author
| |
Collapse
|
|
23
|
Anwar S, Malik JA, Ahmed S, Kameshwar VA, Alanazi J, Alamri A, Ahemad N. Can Natural Products Targeting EMT Serve as the Future Anticancer Therapeutics? MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27227668. [PMID: 36431766 PMCID: PMC9698579 DOI: 10.3390/molecules27227668] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/24/2022] [Accepted: 11/01/2022] [Indexed: 11/09/2022]
Abstract
Cancer is the leading cause of death and has remained a big challenge for the scientific community. Because of the growing concerns, new therapeutic regimens are highly demanded to decrease the global burden. Despite advancements in chemotherapy, drug resistance is still a major hurdle to successful treatment. The primary challenge should be identifying and developing appropriate therapeutics for cancer patients to improve their survival. Multiple pathways are dysregulated in cancers, including disturbance in cellular metabolism, cell cycle, apoptosis, or epigenetic alterations. Over the last two decades, natural products have been a major research interest due to their therapeutic potential in various ailments. Natural compounds seem to be an alternative option for cancer management. Natural substances derived from plants and marine sources have been shown to have anti-cancer activity in preclinical settings. They might be proved as a sword to kill cancerous cells. The present review attempted to consolidate the available information on natural compounds derived from plants and marine sources and their anti-cancer potential underlying EMT mechanisms.
Collapse
Affiliation(s)
- Sirajudheen Anwar
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail 81422, Saudi Arabia
- Molecular Diagnostics Unit and Personalized Treatment, University of Hail, Hail 81422, Saudi Arabia
- Correspondence:
| | - Jonaid Ahmad Malik
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Guwahati 781101, Assam, India
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar 140001, Punjab, India
| | - Sakeel Ahmed
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad 382355, Gujarat, India
| | - Verma Abhishek Kameshwar
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi 641112, Kerala, India
| | - Jowaher Alanazi
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail 81422, Saudi Arabia
- Molecular Diagnostics Unit and Personalized Treatment, University of Hail, Hail 81422, Saudi Arabia
| | - Abdulwahab Alamri
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail 81422, Saudi Arabia
- Molecular Diagnostics Unit and Personalized Treatment, University of Hail, Hail 81422, Saudi Arabia
| | - Nafees Ahemad
- School of Pharmacy, Monash University Malaysia, Jalan lagoon Selatan, Bandar Sunway, Petaling Jaya 47500, Selangor DE, Malaysia
| |
Collapse
|
|
24
|
Onyiba CI, Scarlett CJ, Weidenhofer J. The Mechanistic Roles of Sirtuins in Breast and Prostate Cancer. Cancers (Basel) 2022; 14:cancers14205118. [PMID: 36291902 PMCID: PMC9600935 DOI: 10.3390/cancers14205118] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/06/2022] [Accepted: 10/14/2022] [Indexed: 12/02/2022] Open
Abstract
Simple Summary There are diverse reports of the dual role of sirtuin genes and proteins in breast and prostate cancers. This review discusses the current information on the tumor promotion or suppression roles of SIRT1–7 in breast and prostate cancers. Precisely, we highlight that sirtuins regulate various proteins implicated in proliferation, apoptosis, autophagy, chemoresistance, invasion, migration, and metastasis of both breast and prostate cancer. We also provide evidence of the direct regulation of sirtuins by miRNAs, highlighting the consequences of this regulation in breast and prostate cancer. Overall, this review reveals the potential value of sirtuins as biomarkers and/or targets for improved treatment of breast and prostate cancers. Abstract Mammalian sirtuins (SIRT1–7) are involved in a myriad of cellular processes, including apoptosis, proliferation, differentiation, epithelial-mesenchymal transition, aging, DNA repair, senescence, viability, survival, and stress response. In this review, we discuss the current information on the mechanistic roles of SIRT1–7 and their downstream effects (tumor promotion or suppression) in cancers of the breast and prostate. Specifically, we highlight the involvement of sirtuins in the regulation of various proteins implicated in proliferation, apoptosis, autophagy, chemoresistance, invasion, migration, and metastasis of breast and prostate cancer. Additionally, we highlight the available information regarding SIRT1–7 regulation by miRNAs, laying much emphasis on the consequences in the progression of breast and prostate cancer.
Collapse
Affiliation(s)
- Cosmos Ifeanyi Onyiba
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Ourimbah, NSW 2258, Australia
- Correspondence:
| | - Christopher J. Scarlett
- School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Ourimbah, NSW 2258, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Judith Weidenhofer
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Ourimbah, NSW 2258, Australia
- Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| |
Collapse
|
|
25
|
Min WL, Wang BF, Liang BB, Zhang L, Pan JY, Huang Y, Zhao Y, Lin S, Zhao YH, Zhang SQ, Ma QY. A ROS/Akt/NF-κB Signaling Cascade Mediates Epidermal Growth Factor-Induced Epithelial-Mesenchymal Transition and Invasion in Human Breast Cancer Cells. World J Oncol 2022; 13:289-298. [PMID: 36406192 PMCID: PMC9635793 DOI: 10.14740/wjon1518] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 08/23/2022] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND As one of the most widely used anti-diabetic drugs for type II diabetes, metformin has been shown to exhibit anti-cancer activity in recent years. Epidermal growth factor (EGF) and its receptor, EGFR, play important roles in cancer metastasis in various tumors, including breast cancer. Epithelial-mesenchymal transition (EMT) is a critical process for cancer invasion and metastasis. In this study, we use EGF as a metastatic inducer to investigate the effect of metformin on cancer cell migration, invasion and EMT. METHODS Human breast cancer MCF-7 cells were exposed to EGF with or without metformin or N-acetyl cysteine (NAC). The effects of metformin on breast cancer cell proliferation were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The production of reactive oxygen species (ROS) was tested using 2,7-dichlorodihydrofluorecein diacetate (DCFH-DA). The migratory and invasive abilities of tumor cells were analyzed using wound healing assay and transwell invasion assay, respectively. The expressions of E-cadherin, N-cadherin and Snail were tested using real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting at mRNA and protein levels. The activation of protein kinase B (Akt) and nuclear factor kappa B (NF-κB) were measured by western blotting. RESULTS Our results showed that metformin inhibited breast cancer cell proliferation in a dose-dependent manner with or without EGF. EGF-induced alterations in cell morphology that are characteristic of EMT were reversed by metformin. Metformin also inhibited the EGF-modulated expression of E-cadherin, N-cadherin and Snail and further suppressed cell invasion and migration. In addition, metformin suppressed EGF-induced phosphorylation of Akt and NF-κB. ROS is involved in EGF-induced cancer invasion and activation of phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB pathway. CONCLUSION Taken together, these data indicate that metformin suppresses EGF-induced breast cancer cell migration, invasion and EMT through the inhibition of the PI3K/Akt/NF-κB pathway. These results provide a novel mechanism to explain the role of metformin as a potent anti-metastatic agent in breast cancer cells.
Collapse
Affiliation(s)
- Wei Li Min
- Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China,These authors contributed equally to this work.,Corresponding Author: Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China.
| | - Bao Feng Wang
- Department of Radiation Therapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, China,These authors contributed equally to this work
| | - Bao Bao Liang
- Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Lun Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, China
| | - Ji Yuan Pan
- Department of Radiation Therapy, Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, China
| | - Yi Huang
- Department of Ultrasound, Xi’an Chest Hospital, Xi’an 710061, China
| | - Yang Zhao
- Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Shuai Lin
- Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Yi Han Zhao
- Special Stomatology Department, College of Stomatology, Xi’an Jiaotong University, Xi’an 710004, China
| | - Shu Qun Zhang
- Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
| | - Qing Yong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, China
| |
Collapse
|
|
26
|
Chang JW, Seo ST, Im MA, Won HR, Liu L, Oh C, Jin YL, Piao Y, Kim HJ, Kim JT, Jung SN, Koo BS. Claudin-1 mediates progression by regulating EMT through AMPK/TGF-β signaling in head and neck squamous cell carcinoma. Transl Res 2022; 247:58-78. [PMID: 35462077 DOI: 10.1016/j.trsl.2022.04.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 03/14/2022] [Accepted: 04/12/2022] [Indexed: 01/14/2023]
Abstract
Claudin-1 (CLDN1), a major component of tight junction complexes in the epithelium, maintains cellular polarity, and plays a critical role in cell-to-cell communication as well as epithelial cell homeostasis. Although the role of CLDN1 has been widely studied in cancer, its role in the progression and the exact regulatory mechanisms, remain controversial. Using next-generation sequencing, we first analyzed the expression profiles of tumor/non-tumor paired tissue in patients with head and neck squamous cell carcinoma (HNSC) from public and local cohorts and found out that CLDN1 is upregulated in tumors compared to normal tissues. Next, its correlation with lymph node metastasis and poor prognosis was validated in the retrospective cohort, which collectively suggests CLDN1 as an oncogene in HNSC. As expected, the knockdown of CLDN1 inhibited invasive phenotypes by downregulating epithelial-to-mesenchymal transition (EMT) in vitro. To ascertain the regulatory mechanism of CLDN1 in HNSC analysis of GO term enrichment, KEGG pathways, and curated gene sets were used. As a result, CLDN1 was negatively associated with AMP-activated protein kinase (AMPK) and positively associated with transforming growth factor-β (TGF-β) signaling. In vitro mechanistic assay showed that CLDN1 inhibited AMPK phosphorylation by regulating AMPK upstream phosphatases, which led to inhibition of Smad2 activity. Intriguingly, the invasive phenotype of cancer cells increased by CLDN1 overexpression was rescued by AMPK activation, indicating a role of the CLDN1/AMPK/TGF-β/EMT cascade in HNSC. Consistently in vivo, CLDN1 suppression significantly inhibited the tumor growth, with elevated AMPK expression, suggesting the novel observation of oncogenic CLDN1-AMPK signaling in HNSC.
Collapse
Affiliation(s)
- Jae Won Chang
- Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea
| | - Sung Tae Seo
- Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea
| | - Mi Ae Im
- Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea
| | - Ho-Ryun Won
- Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea
| | - Lihua Liu
- Department of Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea
| | - Chan Oh
- Department of Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea
| | - Yan Li Jin
- Department of Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea
| | - Yudan Piao
- Department of Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea
| | - Hae Jong Kim
- Department of Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea
| | - Jung Tae Kim
- Department of Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea
| | - Seung-Nam Jung
- Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea
| | - Bon Seok Koo
- Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University, School of Medicine, Daejeon, Republic of Korea.
| |
Collapse
|
|
27
|
Sirtuins and Hypoxia in EMT Control. Pharmaceuticals (Basel) 2022; 15:ph15060737. [PMID: 35745656 PMCID: PMC9228842 DOI: 10.3390/ph15060737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 05/25/2022] [Accepted: 06/08/2022] [Indexed: 02/06/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT), a physiological process during embryogenesis, can become pathological in the presence of different driving forces. Reduced oxygen tension or hypoxia is one of these forces, triggering a large number of molecular pathways with aberrant EMT induction, resulting in cancer and fibrosis onset. Both hypoxia-induced factors, HIF-1α and HIF-2α, act as master transcription factors implicated in EMT. On the other hand, hypoxia-dependent HIF-independent EMT has also been described. Recently, a new class of seven proteins with deacylase activity, called sirtuins, have been implicated in the control of both hypoxia responses, HIF-1α and HIF-2α activation, as well as EMT induction. Intriguingly, different sirtuins have different effects on hypoxia and EMT, acting as either activators or inhibitors, depending on the tissue and cell type. Interestingly, sirtuins and HIF can be activated or inhibited with natural or synthetic molecules. Moreover, recent studies have shown that these natural or synthetic molecules can be better conveyed using nanoparticles, representing a valid strategy for EMT modulation. The following review, by detailing the aspects listed above, summarizes the interplay between hypoxia, sirtuins, and EMT, as well as the possible strategies to modulate them by using a nanoparticle-based approach.
Collapse
|
|
28
|
Polvani S, Pepe S, Tempesti S, Tarocchi M, Marroncini G, Bencini L, Ceni E, Mello T, Picariello L, Simeone I, Grappone C, Dragoni G, Antonuzzo L, Giommoni E, Milani S, Galli A. Isoforms of the orphan nuclear receptor COUP‑TFII differentially modulate pancreatic cancer progression. Int J Oncol 2022; 60:55. [PMID: 35348189 PMCID: PMC8997336 DOI: 10.3892/ijo.2022.5345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 02/07/2022] [Indexed: 12/24/2022] Open
Abstract
The expression of the nuclear receptor transcription factor (TF) COUP‑TFII is broadly associated with cell differentiation and cancer development, including of pancreatic ductal adenocarcinoma (PDAC), a devastating disease with one of the poorest prognoses among cancers worldwide. Recent studies have started to investigate the pathological and physiological roles of a novel COUP‑TFII isoform (COUP‑TFII_V2) that lacks the DNA‑binding domain. As the role of the canonical COUP‑TFII in PDAC was previously demonstrated, the present study evaluated whether COUP‑TFII_V2 may have a functional role in PDAC. It was demonstrated that COUP‑TFII_V2 naturally occurs in PDAC cells and in primary samples, where its expression is consistent with shorter overall survival and peripheral invasion. Of note, COUP‑TFII_V2, exhibiting nuclear and cytosolic expression, is linked to epithelial to mesenchymal transition (EMT) and cancer progression, as confirmed by nude mouse experiments. The present results demonstrated that COUP‑TFII_V2 distinctively regulates the EMT of PDAC and, similarly to its sibling, it is associated with tumor aggressiveness. The two isoforms have both overlapping and exclusive functions that cooperate with cancer growth and dissemination. By studying how PDAC cells switch from one isoform to the other, novel insight into cancer biology was gained, indicating that this receptor may serve as a novel possible target for PDAC management.
Collapse
Affiliation(s)
- Simone Polvani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Sara Pepe
- Core Research Laboratory, Institute for Cancer Research and Prevention, I-50139 Florence, Italy
- Department of Medical Biotechnologies, University of Siena, I-53100 Siena, Italy
| | - Sara Tempesti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Mirko Tarocchi
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Giada Marroncini
- Endocrinology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50139 Florence, Italy
| | - Lapo Bencini
- Oncology General Surgery, Azienda Ospedaliero Universitaria Careggi, I-50139 Florence, Italy
| | - Elisabetta Ceni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Tommaso Mello
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Lucia Picariello
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Irene Simeone
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
- Department of Medical Biotechnologies, University of Siena, I-53100 Siena, Italy
| | - Cecilia Grappone
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Lorenzo Antonuzzo
- Department of Experimental and Clinical Medicine, University of Florence, I-50139 Florence, Italy
| | - Elisa Giommoni
- Medical Oncology, Azienda Ospedaliero Universitaria Careggi, I-50139 Florence, Italy
| | - Stefano Milani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| |
Collapse
|
|
29
|
Abstract
In 2011, CAMKK2, the gene encoding calcium/calmodulin-dependent kinase kinase 2 (CAMKK2), was demonstrated to be a direct target of the androgen receptor and a driver of prostate cancer progression. Results from multiple independent studies have confirmed these findings and demonstrated the potential role of CAMKK2 as a clinical biomarker and therapeutic target in advanced prostate cancer using a variety of preclinical models. Drug development efforts targeting CAMKK2 have begun accordingly. CAMKK2 regulation can vary across disease stages, which might have important implications in the use of CAMKK2 as a biomarker. Moreover, new non-cell-autonomous roles for CAMKK2 that could affect tumorigenesis, metastasis and possible comorbidities linked to disease and treatment have emerged and could present novel treatment opportunities for prostate cancer.
Collapse
|
|
30
|
Zheng K, Chen S, Hu X. Peroxisome Proliferator Activated Receptor Gamma Coactivator-1 Alpha: A Double-Edged Sword in Prostate Cancer. Curr Cancer Drug Targets 2022; 22:541-559. [PMID: 35362394 DOI: 10.2174/1568009622666220330194149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/09/2022] [Accepted: 02/17/2022] [Indexed: 12/24/2022]
Abstract
Peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α/PPARGC1A) is a pivotal transcriptional coactivator involved in the regulation of mitochondrial metabolism, including biogenesis and oxidative metabolism. PGC-1α is finely regulated by AMP-activated protein kinases (AMPKs), the role of which in tumors remains controversial to date. In recent years, a growing amount of research on PGC-1α and tumor metabolism has emphasized its importance in a variety of tumors, including prostate cancer (PCA). Compelling evidence has shown that PGC-1α may play dual roles in promoting and inhibiting tumor development under certain conditions. Therefore, a better understanding of the critical role of PGC-1α in PCA pathogenesis will provide new insights into targeting PGC-1α for the treatment of this disease. In this review, we highlight the procancer and anticancer effects of PGC-1α in PCA and aim to provide a theoretical basis for targeting AMPK/PGC-1α to inhibit the development of PCA. In addition, our recent findings provide a candidate drug target and theoretical basis for targeting PGC-1α to regulate lipid metabolism in PCA.
Collapse
Affiliation(s)
- Kun Zheng
- Department of urology, Shanghai Sixth People\'s Hospital, 600 Yishan Road, Xuhui District, Shanghai, China
| | - Suzhen Chen
- Department of Endocrinology and Metabolism, Shanghai Sixth People\'s Hospital, Shanghai Jiao Tong University Affiliated Sixth People\'s Hospital, China
| | - Xiaoyong Hu
- Department of Urology, Shanghai Sixth People\'s Hospital, 600 Yishan Road, Xuhui District, Shanghai, China
| |
Collapse
|
|
31
|
Transcriptional and post-transcriptional control of epithelial-mesenchymal plasticity: why so many regulators? Cell Mol Life Sci 2022; 79:182. [PMID: 35278142 PMCID: PMC8918127 DOI: 10.1007/s00018-022-04199-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 01/18/2022] [Accepted: 02/07/2022] [Indexed: 12/12/2022]
Abstract
The dynamic transition between epithelial-like and mesenchymal-like cell states has been a focus for extensive investigation for decades, reflective of the importance of Epithelial-Mesenchymal Transition (EMT) through development, in the adult, and the contributing role EMT has to pathologies including metastasis and fibrosis. Not surprisingly, regulation of the complex genetic networks that underlie EMT have been attributed to multiple transcription factors and microRNAs. What is surprising, however, are the sheer number of different regulators (hundreds of transcription factors and microRNAs) for which critical roles have been described. This review seeks not to collate these studies, but to provide a perspective on the fundamental question of whether it is really feasible that so many regulators play important roles and if so, what does this tell us about EMT and more generally, the genetic machinery that controls complex biological processes.
Collapse
|
|
32
|
Wang B, Wang M, Jia S, Li T, Yang M, Ge F. Systematic Survey of the Regulatory Networks of the Long Noncoding RNA BANCR in Cervical Cancer Cells. J Proteome Res 2022; 21:1137-1152. [DOI: 10.1021/acs.jproteome.2c00009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Bing Wang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- Key Laboratory of Algal Biology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Min Wang
- The Analysis and Testing Center, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Shuzhao Jia
- The Analysis and Testing Center, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Tao Li
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- Key Laboratory of Algal Biology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Mingkun Yang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- Key Laboratory of Algal Biology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Feng Ge
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- Key Laboratory of Algal Biology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| |
Collapse
|
|
33
|
Uprety B, Abrahamse H. Targeting Breast Cancer and Their Stem Cell Population through AMPK Activation: Novel Insights. Cells 2022; 11:576. [PMID: 35159385 PMCID: PMC8834477 DOI: 10.3390/cells11030576] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Despite some significant advancements, breast cancer has become the most prevalent cancer in the world. One of the main reasons for failure in treatment and metastasis has been attributed to the presence of cancer initiating cells-cancer stem cells. Consequently, research is now being focussed on targeting cancer cells along with their stem cell population. Non-oncology drugs are gaining increasing attention for their potent anticancer activities. Metformin, a drug commonly used to treat type 2 diabetes, is the best example in this regard. It exerts its therapeutic action by activating 5' adenosine monophosphate-activated protein kinase (AMPK). Activated AMPK subsequently phosphorylates and targets several cellular pathways involved in cell growth and proliferation and the maintenance of stem-like properties of cancer stem cells. Therefore, AMPK is emerging as a target of choice for developing effective anticancer drugs. Vanadium compounds are well-known PTP inhibitors and AMPK activators. They find extensive applications in treatment of diabetes and obesity via PTP1B inhibition and AMPK-mediated inhibition of adipogenesis. However, their role in targeting cancer stem cells has not been explored yet. This review is an attempt to establish the applications of insulin mimetic vanadium compounds for the treatment of breast cancer by AMPK activation and PTP1B inhibition pathways.
Collapse
Affiliation(s)
- Bhawna Uprety
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein 2028, South Africa;
| | | |
Collapse
|
|
34
|
Buyuk B, Jin S, Ye K. Epithelial-to-Mesenchymal Transition Signaling Pathways Responsible for Breast Cancer Metastasis. Cell Mol Bioeng 2022; 15:1-13. [PMID: 35096183 PMCID: PMC8761190 DOI: 10.1007/s12195-021-00694-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
Breast carcinoma is highly metastatic and invasive. Tumor metastasis is a convoluted and multistep process involving tumor cell disseminating from their primary site and migrating to the secondary organ. Epithelial-mesenchymal transition (EMT) is one of the crucial steps that initiate cell progression, invasion, and metastasis. During EMT, epithelial cells alter their molecular features and acquire a mesenchymal phenotype. The regulation of EMT is centered by several signaling pathways, including primary mediators TGF-β, Notch, Wnt, TNF-α, Hedgehog, and RTKs. It is also affected by hypoxia and microRNAs (miRNAs). All these pathways are the convergence on the transcriptional factors such as Snail, Slug, Twist, and ZEB1/2. In addition, a line of evidence suggested that EMT and cancer stem like cells (CSCs) are associated. EMT associated cancer stem cells display mesenchymal phenotypes and resist to chemotherapy or targeted therapy. In this review, we highlighted recent discoveries in these signaling pathways and their regulation in breast cancer metastasis and invasion. While the clinical relevance of EMT and breast cancers remains controversial, we speculated a convergent signaling network pivotal to elucidating the transition of epithelial to mesenchymal phenotypes and onset of metastasis of breast cancer cells.
Collapse
Affiliation(s)
- Busra Buyuk
- Department of Biomedical Engineering, Watson College of Engineering and Applied Science, Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), PO Box 6000, Binghamton, NY 13902 USA
| | - Sha Jin
- Department of Biomedical Engineering, Watson College of Engineering and Applied Science, Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), PO Box 6000, Binghamton, NY 13902 USA
| | - Kaiming Ye
- Department of Biomedical Engineering, Watson College of Engineering and Applied Science, Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), PO Box 6000, Binghamton, NY 13902 USA
| |
Collapse
|
|
35
|
Ramchandani D, Berisa M, Tavarez DA, Li Z, Miele M, Bai Y, Lee SB, Ban Y, Dephoure N, Hendrickson RC, Cloonan SM, Gao D, Cross JR, Vahdat LT, Mittal V. Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis. Nat Commun 2021; 12:7311. [PMID: 34911956 PMCID: PMC8674260 DOI: 10.1038/s41467-021-27559-z] [Citation(s) in RCA: 156] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 11/05/2021] [Indexed: 12/26/2022] Open
Abstract
Copper serves as a co-factor for a host of metalloenzymes that contribute to malignant progression. The orally bioavailable copper chelating agent tetrathiomolybdate (TM) has been associated with a significant survival benefit in high-risk triple negative breast cancer (TNBC) patients. Despite these promising data, the mechanisms by which copper depletion impacts metastasis are poorly understood and this remains a major barrier to advancing TM to a randomized phase II trial. Here, using two independent TNBC models, we report a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit elevated intracellular copper levels and a marked sensitivity to TM. Global proteomic and metabolomic profiling identifies TM-mediated inactivation of Complex IV as the primary metabolic defect in the SOX2/OCT4+ cell population. We also identify AMPK/mTORC1 energy sensor as an important downstream pathway and show that AMPK inhibition rescues TM-mediated loss of invasion. Furthermore, loss of the mitochondria-specific copper chaperone, COX17, restricts copper deficiency to mitochondria and phenocopies TM-mediated alterations. These findings identify a copper-metabolism-metastasis axis with potential to enrich patient populations in next-generation therapeutic trials.
Collapse
Affiliation(s)
- Divya Ramchandani
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Mirela Berisa
- Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Diamile A Tavarez
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Zhuoning Li
- Department of Microchemistry and Proteomics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Matthew Miele
- Department of Microchemistry and Proteomics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Yang Bai
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, 10065, USA
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Sharrell B Lee
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Yi Ban
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Noah Dephoure
- Department of Biochemistry, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Ronald C Hendrickson
- Department of Microchemistry and Proteomics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Suzanne M Cloonan
- Department of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- The School of Medicine and Tallaght University Hospital, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Dingcheng Gao
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, 10065, USA
- Department of Cell and Developmental biology, Weill Cornell Medicine, New York, NY, 10065, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Justin R Cross
- Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Linda T Vahdat
- Department of Medicine, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
| | - Vivek Mittal
- Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, 10065, USA.
- Department of Cell and Developmental biology, Weill Cornell Medicine, New York, NY, 10065, USA.
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
| |
Collapse
|
|
36
|
Wang MD, Wang NY, Zhang HL, Sun LY, Xu QR, Liang L, Li C, Huang DS, Zhu H, Yang T. Fatty acid transport protein-5 (FATP5) deficiency enhances hepatocellular carcinoma progression and metastasis by reprogramming cellular energy metabolism and regulating the AMPK-mTOR signaling pathway. Oncogenesis 2021; 10:74. [PMID: 34772914 PMCID: PMC8589992 DOI: 10.1038/s41389-021-00364-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 09/22/2021] [Accepted: 10/11/2021] [Indexed: 12/11/2022] Open
Abstract
Aberrant lipid metabolism is an essential feature of hepatocellular carcinoma (HCC). Fatty acid transport protein-5 (FATP5) is highly expressed in the liver and is involved in the fatty acid transport pathway. However, the potential role of FATP5 in the pathogenesis of HCC remains largely unknown. Herein, we showed that FATP5 was downregulated in HCC tissues and even much lower in vascular tumor thrombi. Low expression of FATP5 was correlated with multiple aggressive and invasive clinicopathological characteristics and contributed to tumor metastasis and a poor prognosis in HCC patients. FATP5 inhibited the epithelial-mesenchymal transition (EMT) process and suppressed HCC cell migration and invasion, while silencing FATP5 had the opposite effects. Mechanistically, knockdown of FATP5 promoted cellular glycolytic flux and ATP production, thus suppressing AMP-activated protein kinase (AMPK) and activating its downstream signaling mammalian target of rapamycin (mTOR) to support HCC progression and metastasis. Activation of AMPK using metformin reversed the EMT program and impaired the metastatic capacity of FATP5-depleted HCC cells. Collectively, FATP5 served as a novel suppressor of HCC progression and metastasis partly by regulating the AMPK/mTOR pathway in HCC, and targeting the FATP5-AMPK axis may be a promising therapeutic strategy for personalized HCC treatment.
Collapse
Affiliation(s)
- Ming-Da Wang
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Nan-Ya Wang
- The Cancer Center, the First Hospital of Jilin University, Changchun, Jilin, China
| | - Hui-Lu Zhang
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Li-Yang Sun
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Qiu-Ran Xu
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China
| | - Lei Liang
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Dong-Sheng Huang
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China.
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China.
| | - Hong Zhu
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Tian Yang
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China.
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China.
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China.
| |
Collapse
|
|
37
|
Wang Y, Dai J, Zeng Y, Guo J, Lan J. E3 Ubiquitin Ligases in Breast Cancer Metastasis: A Systematic Review of Pathogenic Functions and Clinical Implications. Front Oncol 2021; 11:752604. [PMID: 34745984 PMCID: PMC8569917 DOI: 10.3389/fonc.2021.752604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/04/2021] [Indexed: 02/05/2023] Open
Abstract
Female breast cancer has become the most commonly occurring cancer worldwide. Although it has a good prognosis under early diagnosis and appropriate treatment, breast cancer metastasis drastically causes mortality. The process of metastasis, which includes cell epithelial–mesenchymal transition, invasion, migration, and colonization, is a multistep cascade of molecular events directed by gene mutations and altered protein expressions. Ubiquitin modification of proteins plays a common role in most of the biological processes. E3 ubiquitin ligase, the key regulator of protein ubiquitination, determines the fate of ubiquitinated proteins. E3 ubiquitin ligases target a broad spectrum of substrates. The aberrant functions of many E3 ubiquitin ligases can affect the biological behavior of cancer cells, including breast cancer metastasis. In this review, we provide an overview of these ligases, summarize the metastatic processes in which E3s are involved, and comprehensively describe the roles of E3 ubiquitin ligases. Furthermore, we classified E3 ubiquitin ligases based on their structure and analyzed them with the survival of breast cancer patients. Finally, we consider how our knowledge can be used for E3s’ potency in the therapeutic intervention or prognostic assessment of metastatic breast cancer.
Collapse
Affiliation(s)
- Yingshuang Wang
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiawen Dai
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Youqin Zeng
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinlin Guo
- Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jie Lan
- Department of Thoracic Oncology, Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
38
|
Wu C, Zhu M, Lu Z, Zhang Y, Li L, Li N, Yin L, Wang H, Song W, Xu H. L-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis. Nutr Metab (Lond) 2021; 18:98. [PMID: 34724970 PMCID: PMC8559414 DOI: 10.1186/s12986-021-00623-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 09/04/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Recent studies suggest potential benefits of applying L-carnitine in the treatment of cancer cachexia, but the precise mechanisms underlying these benefits remain unknown. This study was conducted to determine the mechanism by which L-carnitine reduces cancer cachexia. METHODS C2C12 cells were differentiated into myotubes by growing them in DMEM for 24 h (hrs) and then changing the media to DMEM supplemented with 2% horse serum. Differentiated myotubes were treated for 2 h with TNF-α to establish a muscle atrophy cell model. After treated with L-carnitine, protein expression of MuRF1, MaFbx, FOXO3, p-FOXO3a, Akt, p-Akt, p70S6K and p-p70S6K was determined by Western blotting. Then siRNA-Akt was used to determine that L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx. In vivo, the cancer cachexia model was established by subcutaneously transplanting CT26 cells into the left flanks of the BALB/c nude mice. After treated with L-carnitine, serum levels of IL-1, IL-6 and TNF-α, and the skeletal muscle content of MuRF1, MaFbx, FOXO3, p-FOXO3a, Akt, p-Akt, p70S6K and p-p70S6K were measured. RESULTS L-carnitine increased the gastrocnemius muscle (GM) weight in the CT26-bearing cachexia mouse model and the cross-sectional fiber area of the GM and myotube diameters of C2C12 cells treated with TNF-α. Additionally, L-carnitine reduced the protein expression of MuRF1, MaFbx and FOXO3a, and increased the p-FOXO3a level in vivo and in vitro. Inhibition of Akt, upstream of FOXO3a, reversed the effects of L-carnitine on the FOXO3a/MaFbx pathway and myotube diameters, without affecting FOXO3a/MuRF-1. In addition to regulating the ubiquitination of muscle proteins, L-carnitine also increased the levels of p-p70S6K and p70S6K, which are involved in protein synthesis. Akt inhibition did not reverse the effects of L-carnitine on p70S6K and p-p70S6K. Hence, L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx and p70S6K pathways. Moreover, L-carnitine reduced the serum levels of IL-1 and IL-6, factors known to induce cancer cachexia. However, there were minimal effects on TNF-α, another inducer of cachexia, in the in vivo model. CONCLUSION These results revealed a novel mechanism by which L-carnitine protects muscle cells and reduces inflammation related to cancer cachexia.
Collapse
Affiliation(s)
- Changpeng Wu
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Changjiangzhilu 10#, Chongqing, China
| | - Mingxing Zhu
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Changjiangzhilu 10#, Chongqing, China
| | - Zongliang Lu
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Changjiangzhilu 10#, Chongqing, China
| | - Yaowen Zhang
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Changjiangzhilu 10#, Chongqing, China
| | - Long Li
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Changjiangzhilu 10#, Chongqing, China
| | - Na Li
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Changjiangzhilu 10#, Chongqing, China
| | - Liangyu Yin
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Changjiangzhilu 10#, Chongqing, China
| | - He Wang
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Changjiangzhilu 10#, Chongqing, China
| | - Wei Song
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Changjiangzhilu 10#, Chongqing, China
| | - Hongxia Xu
- Department of Clinical Nutrition, Daping Hospital, Army Medical University (Third Military Medical University), Changjiangzhilu 10#, Chongqing, China.
| |
Collapse
|
|
39
|
Yu H, Huang Y, Ge Y, Hong X, Lin X, Tang K, Wang Q, Yang Y, Sun W, Huang Y, Luo H. Selenite-induced ROS/AMPK/FoxO3a/GABARAPL-1 signaling pathway modulates autophagy that antagonize apoptosis in colorectal cancer cells. Discov Oncol 2021; 12:35. [PMID: 35201430 PMCID: PMC8777540 DOI: 10.1007/s12672-021-00427-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 08/26/2021] [Indexed: 01/14/2023] Open
Abstract
Previous studies have shown that selenium possessed chemotherapeutic effect against multiple malignant cancers, inducing diverse stress responses including apoptosis and autophagy. Selenite was previously shown to induce apoptosis and autophagy in colorectal cancer cells. However, the relationship between selenite-induced apoptosis and autophagy was not fully understood. Our results revealed a pro-survival role of selenite-induced autophagy against apoptosis in colorectal cancer cells. Real-time PCR array of autophagy-related genes showed that GABARAPL-1 was significantly upregulated in colorectal cancer cells, which was confirmed by western blot and immunofluorescence results. Knockdown of GABARAPL-1 significantly inhibited selenite-induced autophagy and enhanced apoptosis. Furthermore, we found that selenite-induced upregulation of GABARAPL-1 was caused by upregulated p-AMPK and FoxO3a level. Their interaction was correlated with involved in regulation of GABARAPL-1. We observed that activation and inhibition of AMPK influenced both autophagy and apoptosis level via FoxO3a/ GABARAPL-1 signaling, implying the pro-survival role of autophagy against apoptosis. Importantly, we corroborated these findings in a colorectal cancer xenograft animal model with immunohistochemistry and western blot results. Collectively, these results show that sodium selenite could induce ROS/AMPK/FoxO3a/GABARAPL-1-mediated autophagy and downregulate apoptosis in both colorectal cancer cells and colon xenograft model. These findings help to explore sodium selenite as a potential anti-cancer drug in clinical practices.
Collapse
Affiliation(s)
- Hailing Yu
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, No.52 of Meihua Dong Road, Xiangzhou District, Zhuhai, Guangdong Province, China
| | - Yin Huang
- Department of Cardiology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Yanming Ge
- Department of Pharmacy, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Xiaopeng Hong
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Xi Lin
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, No.52 of Meihua Dong Road, Xiangzhou District, Zhuhai, Guangdong Province, China
| | - Kexin Tang
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, No.52 of Meihua Dong Road, Xiangzhou District, Zhuhai, Guangdong Province, China
| | - Qiang Wang
- The Green Aerotechnics Research Institute of Chongqing Jiaotong University, Chongqing, China
| | - Yang Yang
- Institute of Basic Medical Sciences, Peking Union Medical College, Beijing, China
| | - Weiming Sun
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, No.52 of Meihua Dong Road, Xiangzhou District, Zhuhai, Guangdong Province, China
| | - Yongquan Huang
- Department of Ultrasound, The Fifth Affiliated Hospital, Sun Yat-Sen University, No.52 of Meihua Dong Road, Xiangzhou District, Zhuhai, Guangdong Province, China.
| | - Hui Luo
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, No.52 of Meihua Dong Road, Xiangzhou District, Zhuhai, Guangdong Province, China.
| |
Collapse
|
|
40
|
Nagayama D, Saiki A, Shirai K. The Anti-Cancer Effect of Pitavastatin May Be a Drug-Specific Effect: Subgroup Analysis of the TOHO-LIP Study. Vasc Health Risk Manag 2021; 17:169-173. [PMID: 33953560 PMCID: PMC8092348 DOI: 10.2147/vhrm.s306540] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 04/09/2021] [Indexed: 12/31/2022] Open
Abstract
The significance of statin treatment for the reduction of cardiovascular (CV) disease has been reported, whereas other reports have also described anti-cancer properties associated with the class effect of statins. However, the differences in anti-cancer effect of various types of statins have rarely been examined. Pitavastatin is a statin with a different chemical structure and pharmacokinetics from other statins, and the mechanism of the specific anti-cancer effect of pitavastatin has been reported in in vivo therapeutic models. We previously revealed that pitavastatin therapy was superior to atorvastatin therapy in the prevention of CV events, despite similar LDL-cholesterol-lowering effect in the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP). Furthermore, in subgroup analysis of the TOHO-LIP study, cumulative 240-week incidence of new cancer cases tended to be lower in the pitavastatin group compared to the atorvastatin group [0.32% (1/312) vs 1.94% (6/310), log-rank P=0.051]. This finding might reveal the superiority of pitavastatin to prevent carcinogenesis. The molecular mechanism by which pitavastatin suppresses the incidence of any-organ cancer is gradually elucidated, and new combination of cancer treatments with pitavastatin will be developed in the future to further enhance the anti-cancer activity and reduce the side effects.
Collapse
Affiliation(s)
- Daiji Nagayama
- Department of Internal Medicine, Nagayama Clinic, Tochigi, Japan.,Center of Diabetes, Endocrine and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
| | - Atsuhito Saiki
- Center of Diabetes, Endocrine and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
| | - Kohji Shirai
- Department of Internal Medicine, Mihama Hospital, Chiba, Japan
| |
Collapse
|
|
41
|
Hsieh MJ, Weng CC, Lin YC, Wu CC, Chen LT, Cheng KH. Inhibition of β-Catenin Activity Abolishes LKB1 Loss-Driven Pancreatic Cystadenoma in Mice. Int J Mol Sci 2021; 22:ijms22094649. [PMID: 33924999 PMCID: PMC8125161 DOI: 10.3390/ijms22094649] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 01/02/2023] Open
Abstract
Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and remains one of our most recalcitrant and dismal diseases. In contrast to many other malignancies, there has not been a significant improvement in patient survival over the past decade. Despite advances in our understanding of the genetic alterations associated with this disease, an incomplete understanding of the underlying biology and lack of suitable animal models have hampered efforts to develop more effective therapies. LKB1 is a tumor suppressor that functions as a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), which is an important mediator in the regulation of cell growth and epithelial polarity pathways. LKB1 is mutated in a significant number of Peutz–Jeghers syndrome (PJS) patients and in a small proportion of sporadic cancers, including PC; however, little is known about how LKB1 loss contributes to PC development. Here, we report that a reduction in Wnt/β-catenin activity is associated with LKB1 tumor-suppressive properties in PC. Remarkably, in vivo functional analyses of β-catenin in the Pdx-1-Cre LKB1L/L β-cateninL/L mouse model compared to LKB1 loss-driven cystadenoma demonstrate that the loss of β-catenin impairs cystadenoma development in the pancreas of Pdx-1Cre LKB1L/L mice and dramatically restores the normal development and functions of the pancreas. This study further determined the in vivo and in vitro therapeutic efficacy of the β-catenin inhibitor FH535 in suppressing LKB1 loss-driven cystadenoma and reducing PC progression that delineates the potential roles of Wnt/β-catenin signaling in PC harboring LKB1 deficiency.
Collapse
MESH Headings
- AMP-Activated Protein Kinase Kinases
- AMP-Activated Protein Kinases/metabolism
- Animals
- Cell Line, Tumor
- Cystadenoma, Mucinous/etiology
- Cystadenoma, Mucinous/metabolism
- Cystadenoma, Mucinous/prevention & control
- Female
- Humans
- Male
- Mice
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Mutation
- Neoplasms, Experimental/genetics
- Neoplasms, Experimental/metabolism
- Pancreas/drug effects
- Pancreas/metabolism
- Pancreas/pathology
- Pancreatic Neoplasms/etiology
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/prevention & control
- Peutz-Jeghers Syndrome/genetics
- Peutz-Jeghers Syndrome/metabolism
- Protein Serine-Threonine Kinases/deficiency
- Protein Serine-Threonine Kinases/genetics
- Sulfonamides/pharmacology
- Wnt Signaling Pathway/drug effects
- beta Catenin/antagonists & inhibitors
- beta Catenin/genetics
Collapse
Affiliation(s)
- Mei-Jen Hsieh
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; (M.-J.H.); (C.-C.W.); (Y.-C.L.); (C.-C.W.)
- Division of Neurology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan
| | - Ching-Chieh Weng
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; (M.-J.H.); (C.-C.W.); (Y.-C.L.); (C.-C.W.)
| | - Yu-Chun Lin
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; (M.-J.H.); (C.-C.W.); (Y.-C.L.); (C.-C.W.)
| | - Chia-Chen Wu
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; (M.-J.H.); (C.-C.W.); (Y.-C.L.); (C.-C.W.)
| | - Li-Tzong Chen
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; (M.-J.H.); (C.-C.W.); (Y.-C.L.); (C.-C.W.)
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Oncology, National Cheng Kung University Hospital, National Cheng Kung University, Tainan 704, Taiwan
- Correspondence: (L.-T.C.); (K.-H.C.)
| | - Kuang-Hung Cheng
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; (M.-J.H.); (C.-C.W.); (Y.-C.L.); (C.-C.W.)
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: (L.-T.C.); (K.-H.C.)
| |
Collapse
|
|
42
|
Hartwig J, Loebel M, Steiner S, Bauer S, Karadeniz Z, Roeger C, Skurk C, Scheibenbogen C, Sotzny F. Metformin Attenuates ROS via FOXO3 Activation in Immune Cells. Front Immunol 2021; 12:581799. [PMID: 33953705 PMCID: PMC8089390 DOI: 10.3389/fimmu.2021.581799] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 03/31/2021] [Indexed: 12/16/2022] Open
Abstract
Forkhead box O 3 (FOXO3) is a transcription factor involved in cell metabolism, inflammation and longevity. Here, we investigated if metformin can activate FOXO3 in human immune cells and affects the subsequent level of reactive oxygen/nitrogen species (ROS/RNS) in immune cells. AMP-activated protein kinase (AMPK) and FOXO3 activation were investigated by immunoblot or flow cytometry (FC) analysis, respectively. FOXO3 target gene expression was quantified by real-time PCR. ROS/RNS measurement using dichlorodihydrofluorescein diacetate (DCFH-DA) dye was investigated by FC. The role of the FOXO3 single nucleotide polymorphisms (SNPs) rs12212067, rs2802292 and rs12206094 on ROS/RNS production was studied using allelic discrimination PCR. Metformin induced activation of AMPK (pT172) and FOXO3 (pS413). ROS/RNS level was reduced in immune cells after metformin stimulation accompanied by induction of the FOXO3 targets mitochondrial superoxide dismutase and cytochrome c. Studies in Foxo3 deficient (Foxo3-/- ) mouse splenocytes confirmed that metformin mediates its effects via Foxo3 as it attenuates ROS/RNS in myeloid cells of wildtype (WT) but not of Foxo3-/- mice. Our results suggest that FOXO3 can be activated by metformin leading to reduced ROS/RNS level in immune cells. This may add to the beneficial clinical effects of metformin observed in large cohort studies on longevity, cardiovascular and cancer risk.
Collapse
Affiliation(s)
- Jelka Hartwig
- Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität (FU) Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Berlin, Germany
| | - Madlen Loebel
- Science Center, Carl-Thiem-Klinikum Cottbus, Cottbus, Germany
| | - Sophie Steiner
- Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität (FU) Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Berlin, Germany
| | - Sandra Bauer
- Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität (FU) Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Berlin, Germany
| | - Zehra Karadeniz
- Department of Cardiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Carsten Roeger
- Department of Cardiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Carsten Skurk
- Department of Cardiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research) Partner Site Berlin, Berlin, Germany
| | - Carmen Scheibenbogen
- Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität (FU) Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Berlin, Germany
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany
| | - Franziska Sotzny
- Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität (FU) Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health (BIH), Berlin, Germany
| |
Collapse
|
|
43
|
Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells. Sci Rep 2021; 11:2557. [PMID: 33510179 PMCID: PMC7844056 DOI: 10.1038/s41598-021-81172-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with marked resistance to chemotherapeutics without therapies. The tumour microenvironment of iCCA is enriched of Cancer-Stem-Cells expressing Epithelial-to-Mesenchymal Transition (EMT) traits, being these features associated with aggressiveness and drug resistance. Treatment with the anti-diabetic drug Metformin, has been recently associated with reduced incidence of iCCA. We aimed to evaluate the anti-cancerogenic effects of Metformin in vitro and in vivo on primary cultures of human iCCA. Our results showed that Metformin inhibited cell proliferation and induced dose- and time-dependent apoptosis of iCCA. The migration and invasion of iCCA cells in an extracellular bio-matrix was also significantly reduced upon treatments. Metformin increased the AMPK and FOXO3 and induced phosphorylation of activating FOXO3 in iCCA cells. After 12 days of treatment, a marked decrease of mesenchymal and EMT genes and an increase of epithelial genes were observed. After 2 months of treatment, in order to simulate chronic administration, Cytokeratin-19 positive cells constituted the majority of cell cultures paralleled by decreased Vimentin protein expression. Subcutaneous injection of iCCA cells previously treated with Metformin, in Balb/c-nude mice failed to induce tumour development. In conclusion, Metformin reverts the mesenchymal and EMT traits in iCCA by activating AMPK-FOXO3 related pathways suggesting it might have therapeutic implications.
Collapse
|
|
44
|
Wang F, Chen X, Sun B, Ma Y, Niu W, Zhai J, Sun Y. Hypermethylation-mediated downregulation of lncRNA PVT1 promotes granulosa cell apoptosis in premature ovarian insufficiency via interacting with Foxo3a. J Cell Physiol 2021; 236:5162-5175. [PMID: 33393111 DOI: 10.1002/jcp.30222] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/02/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023]
Abstract
Long noncoding RNA PVT1 is involved in the progression of female gynecological cancers. However, the role of PVT1 in ovarian granulosa cell apoptosis-mediated premature ovarian insufficiency (POI) remains unclear. This study aims to elucidate the role of PVT1 in ovarian granulosa cell apoptosis-mediated POI. The expression of PVT1 was compared between ovarian tissues from POI patients and normal controls. The methylation level in the PVT1 promoter region was detected by methylation-specific polymerase chain reaction. The interaction between PVT1 and forkhead box class O3A (Foxo3a) was confirmed by RNA pull-down and RNA immunoprecipitation assays. Granulosa cell apoptosis was detected using flow cytometry. The effect of PVT1 on transcription activity of Foxo3a was detected by luciferase reporter assay. The expression of PVT1 was low in the POI ovarian tissues compared with the controls, and such a low expression was related to the hypermethylation of the PVT1 promoter. PVT1 was localized in both the cytoplasm and the nucleus of granulosa cells. We determined that PVT1 could bind with Foxo3a and that downregulating PVT1 by small interfering RNAs inhibited Foxo3a phosphorylation by promoting SCP4-mediated Foxo3a dephosphorylation, resulting in an increase in Foxo3a transcription activity. Moreover, downregulating PVT1 promoted granulosa cell apoptosis by increasing the Foxo3a protein levels. An in vivo experiment showed that the injection of PVT1 overexpressing vectors restored the ovarian function in POI mice. Hypermethylation-induced downregulation of PVT1 promotes granulosa cell apoptosis in POI by inhibiting Foxo3a phosphorylation and increases the Foxo3a transcription activity.
Collapse
Affiliation(s)
- Fang Wang
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xuemei Chen
- Department of Human Anatomy, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Bo Sun
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yujia Ma
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Wenbin Niu
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jun Zhai
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yingpu Sun
- Reproductive Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| |
Collapse
|
|
45
|
Song Y, Zeng S, Zheng G, Chen D, Li P, Yang M, Luo K, Yin J, Gu Y, Zhang Z, Jia X, Qiu N, He Z, Li H, Liu H. FOXO3a-driven miRNA signatures suppresses VEGF-A/NRP1 signaling and breast cancer metastasis. Oncogene 2020; 40:777-790. [PMID: 33262463 PMCID: PMC7843418 DOI: 10.1038/s41388-020-01562-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 10/19/2020] [Accepted: 11/11/2020] [Indexed: 12/21/2022]
Abstract
Metastasis remains the major obstacle to improved survival for breast cancer patients. Downregulation of FOXO3a transcription factor in breast cancer is causally associated with the development of metastasis through poorly understood mechanisms. Here, we report that FOXO3a is functionally related to the inhibition of VEGF-A/NRP1 signaling and to the consequent suppression of breast cancer metastasis. We show that FOXO3a directly induces miR-29b-2 and miR-338 expression. Ectopic expression of miR-29b-2/miR-338 significantly suppresses EMT, migration/invasion, and in vivo metastasis of breast cancer. Moreover, we demonstrate that miR-29b-2 directly targets VEGF-A while miR-338 directly targets NRP1, and show that regulation of miR-29b-2 and miR-338 mediates the ability of FOXO3a to suppress VEGF-A/NRP1 signaling and breast cancer metastasis. Clinically, our results show that the FOXO3a-miR-29b-2/miR-338-VEGF-A/NRP1 axis is dysregulated and plays a critical role in disease progression in breast cancer. Collectively, our findings propose that FOXO3a functions as a metastasis suppressor, and define a novel signaling axis of FOXO3a-miRNA-VEGF-A/NRP1 in breast cancer, which might be potential therapeutic targets for breast cancer.
Collapse
Affiliation(s)
- Ying Song
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Shanshan Zeng
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Guopei Zheng
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Danyang Chen
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Pan Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Mingqiang Yang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Kai Luo
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Jiang Yin
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Yixue Gu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Zhijie Zhang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Xiaoting Jia
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Ni Qiu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China
| | - Zhimin He
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China.
| | - Hongsheng Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China.
| | - Hao Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou, 510095, PR China.
| |
Collapse
|
|
46
|
Yuan J, Dong X, Yap J, Hu J. The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy. J Hematol Oncol 2020; 13:113. [PMID: 32807225 PMCID: PMC7433213 DOI: 10.1186/s13045-020-00949-4] [Citation(s) in RCA: 309] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways. The Ras/RAF/MEK/ERK (MAPK) signaling is one of the best-defined pathways in cancer biology, and its hyperactivation is responsible for over 40% human cancer cases. To drive carcinogenesis, this signaling promotes cellular overgrowth by turning on proliferative genes, and simultaneously enables cells to overcome metabolic stress by inhibiting AMPK signaling, a key singular node of cellular metabolism. Recent studies have shown that AMPK signaling can also reversibly regulate hyperactive MAPK signaling in cancer cells by phosphorylating its key components, RAF/KSR family kinases, which affects not only carcinogenesis but also the outcomes of targeted cancer therapies against the MAPK signaling. In this review, we will summarize the current proceedings of how MAPK-AMPK signalings interplay with each other in cancer biology, as well as its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators, and discuss the exploitation of combinatory therapies targeting both MAPK and AMPK as a novel therapeutic intervention.
Collapse
Affiliation(s)
- Jimin Yuan
- Department of Urology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
- Geriatric Department, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
| | - Xiaoduo Dong
- Shenzhen People's Hospital, 1017 Dongmen North Road, Shenzhen, 518020, China
| | - Jiajun Yap
- Cancer and Stem Cell Program, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Jiancheng Hu
- Cancer and Stem Cell Program, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
| |
Collapse
|
|
47
|
Matheson CJ, Casalvieri KA, Backos DS, Minhajuddin M, Jordan CT, Reigan P. Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors. Eur J Med Chem 2020; 197:112316. [PMID: 32334266 PMCID: PMC7409528 DOI: 10.1016/j.ejmech.2020.112316] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 12/05/2019] [Accepted: 04/06/2020] [Indexed: 12/22/2022]
Abstract
AMP-activated protein kinase (AMPK) is a central metabolic regulator that promotes cancer growth and survival under hypoxia and plays a role in the maintenance of cancer stem cells. A major challenge to interrogating the potential of targeting AMPK in cancer is the lack of potent and selective small molecule inhibitors. Compound C has been widely used as an AMPK inhibitor, but it lacks potency and has a poor selectivity profile. The multi-kinase inhibitor, sunitinib, has demonstrated potent nanomolar inhibition of AMPK activity and has scope for modification. Here, we have designed and synthesized several series of oxindoles to determine the structural requirements for AMPK inhibition and to improve selectivity. We identified two potent, novel oxindole-based AMPK inhibitors that were designed to interact with the DFG motif in the ATP-binding site of AMPK, this key feature evades interaction with the common recptor tyrosine kinase targets of sunitinib. Cellular engagement of AMPK by these oxindoles was confirmed by the inhibition of phosphorylation of acetyl-CoA carboxylase (ACC), a known substrate of AMPK, in myeloid leukemia cells. Interestingly, although AMPK is highly expressed and activated in K562 cells these oxindole-based AMPK inhibitors did not impact cell viability or result in significant cytotoxicity. Our studies serve as a platform for the further development of oxindole-based AMPK inhibitors with therapeutic potential.
Collapse
Affiliation(s)
- Christopher J Matheson
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA
| | - Kimberly A Casalvieri
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA
| | - Donald S Backos
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA
| | - Mohammed Minhajuddin
- Division of Hematology, University of Colorado Anschutz Medical Campus, 12700 E 19th Avenue, Aurora, CO, 80045, USA
| | - Craig T Jordan
- Division of Hematology, University of Colorado Anschutz Medical Campus, 12700 E 19th Avenue, Aurora, CO, 80045, USA
| | - Philip Reigan
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA.
| |
Collapse
|
|
48
|
AMP-activated protein kinase regulates alternative pre-mRNA splicing by phosphorylation of SRSF1. Biochem J 2020; 477:2237-2248. [DOI: 10.1042/bcj20190894] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 05/21/2020] [Accepted: 05/26/2020] [Indexed: 01/23/2023]
Abstract
AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic processes and activating catabolic processes. Recent studies have demonstrated that metformin, which is an AMPK activator, modifies alternative precursor mRNA (pre-mRNA) splicing. However, no direct substrate of AMPK for alternative pre-mRNA splicing has been reported. In the present study, we identified the splicing factor serine/arginine-rich splicing factor 1 (SRSF1) as a novel AMPK substrate. AMPK directly phosphorylated SRSF1 at Ser133 in an RNA recognition motif. Ser133 phosphorylation suppressed the interaction between SRSF1 and specific RNA sequences without altering the subcellular localization of SRSF1. Moreover, AMPK regulated the SRSF1-mediated alternative pre-mRNA splicing of Ron, which is a macrophage-stimulating protein receptor, by suppressing its interaction with exon 12 of Ron pre-mRNA. The findings of this study revealed that the AMPK-dependent phosphorylation of SRSF1 at Ser133 inhibited the ability of SRSF1 to bind RNA and regulated alternative pre-mRNA splicing.
Collapse
|
|
49
|
Feng S, Zhang L, Liu X, Li G, Zhang B, Wang Z, Zhang H, Ma H. Low levels of AMPK promote epithelial-mesenchymal transition in lung cancer primarily through HDAC4- and HDAC5-mediated metabolic reprogramming. J Cell Mol Med 2020; 24:7789-7801. [PMID: 32519437 PMCID: PMC7348170 DOI: 10.1111/jcmm.15410] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 04/15/2020] [Accepted: 05/03/2020] [Indexed: 12/11/2022] Open
Abstract
AMP-activated protein kinase (AMPK) serves as a "supermetabolic regulator" that helps maintain cellular energy homeostasis. However, the role of AMPK in glucose metabolism reprogramming in lung cancer remains unclear. Here, our study shows that low AMPK expression correlates with metastasis and clinicopathologic parameters of non-small-cell lung cancer. Low AMPK significantly enhances the Warburg effect in HBE and A549 cells, which in turn induces the expression of mesenchymal markers and enhances their invasion and migration. At the mechanistic level, low AMPK up-regulates HK2 expression and glycolysis levels through HDAC4 and HDAC5. Collectively, our findings demonstrate that low AMPK-induced metabolism can promote epithelial-mesenchymal transition progression in normal bronchial epithelial cells and lung cancer cells, and increase the risk for tumour metastasis.
Collapse
Affiliation(s)
- Shoujie Feng
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.,Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, China
| | - Li Zhang
- Editorial Office of International Journal of Anesthesiology and Resuscitation, Xuzhou Medical University, Xuzhou, China
| | - Xiucheng Liu
- Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, China
| | - Guangbin Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Biao Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ziwen Wang
- Intensive Care Unit, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Hao Zhang
- Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, China
| | - Haitao Ma
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| |
Collapse
|
|
50
|
Therapeutic aspects of AMPK in breast cancer: Progress, challenges, and future directions. Biochim Biophys Acta Rev Cancer 2020; 1874:188379. [PMID: 32439311 DOI: 10.1016/j.bbcan.2020.188379] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 05/06/2020] [Accepted: 05/10/2020] [Indexed: 12/17/2022]
Abstract
Breast cancer is the most ubiquitous type of neoplasms among women worldwide. Molecular aberrations associated with breast development and progressions have been extensively investigated in recent years. An AMP-activated kinase (AMPK) initially identified as a cellular energy sensor that plays a crucial role in cellular energy homeostasis. Intensive research over the last decade about the molecular mechanisms of AMPK has demonstrated that AMPK mediated diverse biological functions are achieved through phosphorylation and regulation of multiple downstream signaling molecules in normal tissue. Downregulation of AMPK activity or decreased level involved in the promotion of breast tumorigenesis, and thus activation of AMPK found to oppose tumor progression. In this review, we epitomize the recent advances in exploring the tumor suppressor function of AMPK pathways. Besides, we discuss the developments in the area of AMPK activator and its molecular mechanisms for breast cancer treatment.
Collapse
|