1
|
Shaw P, Dey Bhowmik A, Gopinatha Pillai MS, Robbins N, Dwivedi SKD, Rao G. Anoikis resistance in Cancer: Mechanisms, therapeutic strategies, potential targets, and models for enhanced understanding. Cancer Lett 2025; 624:217750. [PMID: 40294841 DOI: 10.1016/j.canlet.2025.217750] [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: 01/21/2025] [Revised: 04/01/2025] [Accepted: 04/26/2025] [Indexed: 04/30/2025]
Abstract
Anoikis, defined as programmed cell death triggered by the loss of cell-extracellular matrix (ECM) and cell-cell interactions, is crucial for maintaining tissue homeostasis and preventing aberrant cell migration. Cancer cells, however, display anoikis resistance (AR) which in turn enables cancer metastasis. AR results from alterations in apoptotic signaling, metabolic reprogramming, autophagy modulation, and epigenetic changes, allowing cancer cells to survive in detached conditions. In this review we describe the mechanisms underlying both anoikis and AR, focusing on intrinsic and extrinsic pathways, disrupted cell-ECM interactions, and autophagy in cancer. Recent findings (i.e., between 2014 and 2024) on epigenetic regulation of AR and its role in metastasis are discussed. Therapeutic strategies targeting AR, including chemical inhibitors, are highlighted alongside a network analysis of 122 proteins reported to be associated with AR which identifies 53 hub proteins as potential targets. We also evaluate in vitro and in vivo models for studying AR, emphasizing their role in advancing metastasis research. Our overall goal is to guide future studies and therapeutic developments to counter cancer metastasis.
Collapse
Affiliation(s)
- Pallab Shaw
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Pathology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Arpan Dey Bhowmik
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Mohan Shankar Gopinatha Pillai
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Nathan Robbins
- James E. Hurley School of Science and Mathematics, Oklahoma Baptist University, Shawnee, OK, USA
| | - Shailendra Kumar Dhar Dwivedi
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Geeta Rao
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Pathology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA.
| |
Collapse
|
2
|
Feng S, Zhang L, Sun T, Xu L, Quan X, Zhao G, Zhang H. OVOL1 Promotes Proliferation and Metastasis of Non-Small Cell Lung Cancer by Regulating APOE-Mediated Cholesterol Metabolism. J Cell Mol Med 2025; 29:e70634. [PMID: 40437660 PMCID: PMC12119240 DOI: 10.1111/jcmm.70634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 05/15/2025] [Accepted: 05/21/2025] [Indexed: 06/01/2025] Open
Abstract
Non-small cell lung cancer (NSCLC) is a highly lethal malignant tumour characterised by its resistance to treatment, often due to metabolic reprogramming. Despite this, the underlying mechanisms by which aberrant cholesterol metabolism influences the development and progression of NSCLC remain unclear. In our study, we observed that OVOL1 is significantly upregulated in NSCLC and is correlated with a poor prognosis. Furthermore, our functional assays revealed that OVOL1 enhances the proliferation and metastasis of NSCLC cells both in vitro and in vivo. Mechanistically, OVOL1 was found to modulate cholesterol reprogramming and increase the expression of APOE, thereby intensifying cholesterol metabolism and facilitating cell migration and invasion. In conclusion, our findings suggest that OVOL1 acts as an oncogene in NSCLC, promoting tumour growth and metastasis through the enhancement of cholesterol metabolism. This underscores the potential of OVOL1 as a therapeutic target for the treatment of NSCLC.
Collapse
Affiliation(s)
- Shoujie Feng
- Thoracic Surgery LaboratoryXuzhou Medical UniversityXuzhouJiangsuChina
- Department of Thoracic SurgeryAffiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| | - Li Zhang
- Editorial Office of International Journal of Anesthesiology and ResuscitationXuzhou Medical UniversityXuzhouJiangsuChina
| | - Teng Sun
- Thoracic Surgery LaboratoryXuzhou Medical UniversityXuzhouJiangsuChina
- Department of Thoracic SurgeryAffiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| | - Lei Xu
- Department of Emergency MedicineThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| | - Xiaoyu Quan
- Thoracic Surgery LaboratoryXuzhou Medical UniversityXuzhouJiangsuChina
- Department of Thoracic SurgeryAffiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| | - Guoqing Zhao
- Thoracic Surgery LaboratoryXuzhou Medical UniversityXuzhouJiangsuChina
- Department of Thoracic SurgeryAffiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| | - Hao Zhang
- Thoracic Surgery LaboratoryXuzhou Medical UniversityXuzhouJiangsuChina
- Department of Thoracic SurgeryAffiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| |
Collapse
|
3
|
Zhang J, Kong X, Zhou B, Li R, Yu Z, Zhu J, Xi Q, Li Y, Zhao Z, Zhang R. Metabolic reprogramming of drug resistance in pancreatic cancer: mechanisms and effects. Mol Aspects Med 2025; 103:101368. [PMID: 40398192 DOI: 10.1016/j.mam.2025.101368] [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: 01/19/2025] [Revised: 05/10/2025] [Accepted: 05/10/2025] [Indexed: 05/23/2025]
Abstract
Pancreatic cancer is a highly aggressive gastrointestinal malignancy, often termed the "king of cancers" due to its notoriously high mortality rate. Its clinical characteristics, including late diagnosis, low surgical resectability, high recurrence rates, significant chemoresistance, and poor prognosis have collectively driven the persistent rise in incidence and mortality. Despite ongoing advancements in therapeutic strategies, the management of pancreatic cancer, particularly at advanced stages, remains challenging. Chemotherapy remains the mainstay of current treatment. However, the prevalent problem of chemotherapy resistance poses a significant obstacle to effective treatment. Metabolic reprogramming, characterized by alterations in glucose metabolism, lipid biosynthesis, and amino acid utilization, supports the high energy demands and rapid proliferation of cancer cells. Emerging evidence suggests that these metabolic changes, possibly mediated by epigenetic mechanisms, also contribute to tumorigenesis and metastasis. These findings highlight the critical role of metabolic alterations in pancreatic cancer pathogenesis. This review explores the relationship between metabolic reprogramming and chemotherapy resistance, discussing underlying mechanisms and summarizing preclinical studies and drug development targeting metabolism. The aim is to provide a comprehensive perspective on potential therapeutic strategies for pancreatic cancer.
Collapse
Affiliation(s)
- Jinyi Zhang
- Guangdong Provincial Key Laboratory for Biotechnology Drug Candidates, Department of Biotechnology, Laboratory of Immunology and Inflammation, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou,The Second Clinical Medical School of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xueqing Kong
- Guangdong Provincial Key Laboratory for Biotechnology Drug Candidates, Department of Biotechnology, Laboratory of Immunology and Inflammation, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou,The Second Clinical Medical School of Guangdong Pharmaceutical University, Guangzhou, China
| | - Boyan Zhou
- Guangdong Provincial Key Laboratory for Biotechnology Drug Candidates, Department of Biotechnology, Laboratory of Immunology and Inflammation, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou,The Second Clinical Medical School of Guangdong Pharmaceutical University, Guangzhou, China
| | - Rui Li
- Guangdong Provincial Key Laboratory for Biotechnology Drug Candidates, Department of Biotechnology, Laboratory of Immunology and Inflammation, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou,The Second Clinical Medical School of Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhaoan Yu
- Guangdong Provincial Key Laboratory for Biotechnology Drug Candidates, Department of Biotechnology, Laboratory of Immunology and Inflammation, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou,The Second Clinical Medical School of Guangdong Pharmaceutical University, Guangzhou, China
| | - Jinrong Zhu
- Guangdong Provincial Key Laboratory for Biotechnology Drug Candidates, Department of Biotechnology, Laboratory of Immunology and Inflammation, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou,The Second Clinical Medical School of Guangdong Pharmaceutical University, Guangzhou, China
| | - Qing Xi
- Guangdong Provincial Key Laboratory for Biotechnology Drug Candidates, Department of Biotechnology, Laboratory of Immunology and Inflammation, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou,The Second Clinical Medical School of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yan Li
- Guangdong Provincial Key Laboratory for Biotechnology Drug Candidates, Department of Biotechnology, Laboratory of Immunology and Inflammation, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou,The Second Clinical Medical School of Guangdong Pharmaceutical University, Guangzhou, China
| | - Zichao Zhao
- Department of Emergency Medicine, Shaodong People's Hospital, Shaodong City, Hunan Province, China.
| | - Rongxin Zhang
- Guangdong Provincial Key Laboratory for Biotechnology Drug Candidates, Department of Biotechnology, Laboratory of Immunology and Inflammation, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou,The Second Clinical Medical School of Guangdong Pharmaceutical University, Guangzhou, China.
| |
Collapse
|
4
|
Hsu CY, Ismaeel GL, Kadhim O, Hadi ZD, Alubiady MHS, Alasheqi MQ, Ali MS, Ramadan MF, Al-Abdeen SHZ, Muzammil K, Balasim HM, Alawady AH. Beyond the brain: Reelin's emerging role in cancer pathways. Pathol Res Pract 2025; 269:155901. [PMID: 40068281 DOI: 10.1016/j.prp.2025.155901] [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: 09/12/2024] [Revised: 03/02/2025] [Accepted: 03/04/2025] [Indexed: 04/19/2025]
Abstract
The glycoprotein Reelin is essential for neuronal migration during embryonic development and is involved in various cellular processes. It interacts with specific lipoprotein receptors to regulate neuronal migration and synaptic plasticity. Recent research has expanded our understanding of Reelin's functions, revealing its involvement in processes such as cell proliferation, activation, migration, platelet aggregation, and vascular development. Reelin's influence extends beyond neurodevelopment, with abnormal expression observed in several cancer types. This suggests a potential connection between Reelin dysregulation and tumor formation. Altered Reelin levels correlate with increased tumor aggressiveness, metastatic potential, and poor patient outcomes. In cancer, Reelin affects key cellular processes including proliferation, migration, and invasion. Evidence indicates that Reelin modulates important signaling pathways like PI3K/Akt and MAPK, contributing to the development of cancer hallmarks. Its interactions with integrins and matrix metalloproteinases imply a role in shaping the tumor microenvironment, thereby influencing cancer progression. These findings highlight Reelin's dual significance in neurodevelopment and cancer biology. Further investigation into Reelin's complex functions could lead to new diagnostic tools and therapeutic approaches, potentially advancing cancer treatment through targeted research on its signaling mechanisms. This review provides a condensed overview of Reelin's multifaceted roles in both neurodevelopment and cancer.
Collapse
Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, AZ, 85004, USA
| | - Ghufran Lutfi Ismaeel
- Department of Pharmacology, College of Pharmacy, University of Al-Ameed, Karbala, Iraq
| | - Oras Kadhim
- Department of Anesthesia Techniques, Al-Manara College For Medical Sciences, Maysan, Iraq
| | - Zaid Dahnoon Hadi
- Department of Anesthesia Techniques, Al-Noor University College, Nineveh, Iraq
| | | | | | | | | | | | - Khursheed Muzammil
- Department of Public Health, College of Applied Medical Sciences, Khamis Mushait Campus, King Khalid University, Abha, Saudi Arabia.
| | - Halah Majeed Balasim
- Department of Medical Laboratory Technologies, Al Rafidain University College, Bagdad, Iraq
| | - Ahmed Hussien Alawady
- College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
| |
Collapse
|
5
|
Ray SK, Mukherjee S. New insights into reductive stress responses and its clinical relation in cancer. Tissue Cell 2025; 93:102736. [PMID: 39826384 DOI: 10.1016/j.tice.2025.102736] [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: 08/22/2024] [Revised: 01/08/2025] [Accepted: 01/08/2025] [Indexed: 01/22/2025]
Abstract
Cells are susceptible to both oxidative and reductive stresses, with reductive stress being less studied and potentially therapeutic in cancer. Reductive stress, characterized by an excess of reducing equivalents exceeding the activity of endogenous oxidoreductases, can lead to an imbalance in homeostasis, causing an increase in reactive oxygen species induction, affecting cellular antioxidant load and flux. Unlike oxidative stress, reductive stress has been understudied and poorly understood, and there is still much to learn about its mechanisms in cancer, its therapeutic potential, and how cancer cells react to it. Changes in redox balance and interference with redox signaling are linked to cancer cell growth, metastasis, and resistance to chemotherapy and radiation. Overconsumption of reducing equivalents can reduce metabolism, alter protein disulfide bond formation, disrupt mitochondrial homeostasis, and disrupt cancer cell signaling pathways. Novel approaches to delivering or using cancer medicines and techniques to influence redox biology have been discovered. Under reductive stress, cancer cells may coordinate separate pools of redox pairs, potentially impacting biology.
Collapse
Affiliation(s)
- Suman Kumar Ray
- Independent Researcher, Bhopal, Madhya Pradesh 462020, India
| | - Sukhes Mukherjee
- Department of Biochemistry. All India Institute of Medical Sciences. Bhopal, Madhya Pradesh 462020, India.
| |
Collapse
|
6
|
Gore M, Kabekkodu SP, Chakrabarty S. Exploring the metabolic alterations in cervical cancer induced by HPV oncoproteins: From mechanisms to therapeutic targets. Biochim Biophys Acta Rev Cancer 2025; 1880:189292. [PMID: 40037419 DOI: 10.1016/j.bbcan.2025.189292] [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: 09/12/2024] [Revised: 02/24/2025] [Accepted: 02/25/2025] [Indexed: 03/06/2025]
Abstract
The role of human Papillomavirus (HPV) in metabolic reprogramming is implicated in the development and progression of cervical cancer. During carcinogenesis, cancer cells modify various metabolic pathways to generate energy and sustain their growth and development. Cervical cancer, one of the most prevalent malignancies affecting women globally, involves metabolic alterations such as increased glycolysis, elevated lactate production, and lipid accumulation. The oncoproteins, primarily E6 and E7, which are encoded by high-risk HPVs, facilitate the accumulation of several cancer markers, promoting not only the growth and development of cancer but also metastasis, immune evasion, and therapy resistance. HPV oncoproteins interact with cellular MYC (c-MYC), retinoblastoma protein (pRB), p53, and hypoxia-inducible factor 1α (HIF-1α), leading to the induction of metabolic reprogramming and favour the Warburg effect. Metabolic reprogramming enables HPV to persist for an extended period and accelerates the progression of cervical cancer. This review summarizes the role of HPV oncoproteins in metabolic reprogramming and their contributions to the development and progression of cervical cancer. Additionally, this review provides insights into how metabolic reprogramming opens avenues for novel therapeutic strategies, including the discovery of new and repurposed drugs that could be applied to treat cervical cancer.
Collapse
Affiliation(s)
- Mrudula Gore
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
| | - Sanjiban Chakrabarty
- Department of Public Health Genomics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| |
Collapse
|
7
|
Jie H, Lai H, Wang Z, Yi M, Liu Y, Urbanska EM, Santoni-Rugiu E, Wei S, Chen Y, Li C, Wang T, Luo N, Liu L, Deng S, Guo C. Targeting of arachidonic acid-modulated autophagy to enhance the sensitivity of ROS1 + or ALK + non-small cell lung cancer to crizotinib therapy. Transl Lung Cancer Res 2025; 14:878-896. [PMID: 40248722 PMCID: PMC12000944 DOI: 10.21037/tlcr-2025-105] [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: 02/23/2025] [Accepted: 03/18/2025] [Indexed: 04/19/2025]
Abstract
Background As an approved targeting drug, crizotinib has been widely used in the treatment of patients with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements or c-ros oncogene 1 (ROS1) fusions and has demonstrated remarkable therapeutic effects. However, crizotinib-treated patients frequently experience drug resistance, and there are still some underlying mechanisms, which remain unclear. Autophagy, a cellular process that involves the degradation and recycling of cellular components, has been implicated in the development of drug resistance. In this study, we aim to elucidate the mechanisms of crizotinib resistance involving autophagy dysregulation and identify novel therapeutic targets to overcome this resistance. Methods We first established a model for crizotinib resistance in HCC78 and H3122 cells. Next, the level of proliferation, apoptosis, autophagy flux, and reactive oxygen species (ROS) of these cells were measured. Subsequently, we analyzed the published single-cell RNA sequencing data from three ALK-rearranged lung cancer organoid samples and performed a metabolomics assay on crizotinib-resistant HCC78 cells. Finally, the therapeutic effects were confirmed in vitro by targeting autophagy flux. Results Crizotinib induced cell apoptosis and growth arrest by promoting the accumulation of autophagosomes through the inhibition of autophagy flux in ROS1 + or ALK + NSCLC. In contrast, crizotinib-resistant NSCLC cells showed inactivation of signal transducer and activator of transcription 3 (STAT3) phosphorylation and downregulation of prostaglandin endoperoxide synthase 2 (PTGS2), leading to an increase in the metabolite arachidonic acid (AA). AA further promoted autophagy flux and reduced autophagosome accumulation, driving crizotinib resistance under conditions of drug stress. Moreover, chloroquine (CQ), anti-malaria drug and lysosome inhibitor developed in 1940, could induce cell death in crizotinib-resistant NSCLC by blocking AA-mediated autophagy flux and facilitating autophagosome accumulation, significantly enhancing the treatment efficacy of crizotinib in drug-resistant NSCLC. Conclusions We discovered a new mechanism of first generation ALK- and ROS1-TKIs resistance, which points to the role of the metabolite AA in resistance to tyrosine kinase inhibitors. It may potentially provide an alternative strategy to overcoming crizotinib resistance in NSCLC treatment by reversing AA-mediated autophagy.
Collapse
Affiliation(s)
- Hui Jie
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Hongjin Lai
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Zihuai Wang
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Min Yi
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Liu
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Edyta Maria Urbanska
- Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Eric Santoni-Rugiu
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Shiyou Wei
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuhao Chen
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Chuan Li
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Tengyong Wang
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Nanzhi Luo
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Lunxu Liu
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Senyi Deng
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Chenglin Guo
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
8
|
Madoz-Gúrpide J, Serrano-López J, Sanz-Álvarez M, Morales-Gallego M, Rodríguez-Pinilla SM, Rovira A, Albanell J, Rojo F. Adaptive Proteomic Changes in Protein Metabolism and Mitochondrial Alterations Associated with Resistance to Trastuzumab and Pertuzumab Therapy in HER2-Positive Breast Cancer. Int J Mol Sci 2025; 26:1559. [PMID: 40004024 PMCID: PMC11855744 DOI: 10.3390/ijms26041559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/30/2025] [Accepted: 02/06/2025] [Indexed: 02/27/2025] Open
Abstract
HER2 (human epidermal growth factor receptor 2) is overexpressed in approximately 15-20% of breast cancers, leading to aggressive tumour growth and poor prognosis. Anti-HER2 therapies, such as trastuzumab and pertuzumab, have significantly improved the outcomes for patients with HER2-positive breast cancer by blocking HER2 signalling. However, intrinsic and acquired resistance remains a major clinical challenge, limiting the long-term effectiveness of these therapies. Understanding the mechanisms of resistance is essential for developing strategies to overcome it and improve the therapeutic outcomes. We generated multiple HER2-positive breast cancer cell line models resistant to trastuzumab and pertuzumab combination therapy. Using mass spectrometry-based proteomics, we conducted a comprehensive analysis to identify the mechanisms underlying resistance. Proteomic analysis identified 618 differentially expressed proteins, with a core of 83 overexpressed and 118 downregulated proteins. Through a series of advanced bioinformatics analyses, we identified significant protein alterations and signalling pathways potentially responsible for the development of resistance, revealing key alterations in the protein metabolism, mitochondrial function, and signalling pathways, such as MAPK, TNF, and TGFβ. These findings identify mitochondrial activity and detoxification processes as pivotal mechanisms underlying the resistance to anti-HER2 therapy. Additionally, we identified key proteins, including ANXA1, SLC2A1, and PPIG, which contribute to the tumour progression and resistance phenotype. Our study suggests that targeting these pathways and proteins could form the basis of novel therapeutic strategies to overcome resistance in HER2-positive breast cancer.
Collapse
Affiliation(s)
- Juan Madoz-Gúrpide
- Department of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, Spain (M.M.-G.); (S.M.R.-P.)
| | - Juana Serrano-López
- Department of Haematology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, Spain;
| | - Marta Sanz-Álvarez
- Department of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, Spain (M.M.-G.); (S.M.R.-P.)
| | - Miriam Morales-Gallego
- Department of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, Spain (M.M.-G.); (S.M.R.-P.)
| | - Socorro María Rodríguez-Pinilla
- Department of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, Spain (M.M.-G.); (S.M.R.-P.)
| | - Ana Rovira
- Cancer Research Program, IMIM (Hospital del Mar Research Institute), 08003 Barcelona, Spain;
| | - Joan Albanell
- Department of Medical Oncology, Hospital del Mar—CIBERONC, 08003 Barcelona, Spain;
| | - Federico Rojo
- Department of Pathology, Fundación Jiménez Díaz University Hospital Health Research Institute (IIS—FJD, UAM)—CIBERONC, 28040 Madrid, Spain (M.M.-G.); (S.M.R.-P.)
| |
Collapse
|
9
|
Wei X, Xiong X, Chen Z, Chen B, Zhang C, Zhang W. MicroRNA155 in non-small cell lung cancer: a potential therapeutic target. Front Oncol 2025; 15:1517995. [PMID: 39963112 PMCID: PMC11830606 DOI: 10.3389/fonc.2025.1517995] [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: 10/27/2024] [Accepted: 01/09/2025] [Indexed: 02/20/2025] Open
Abstract
Lung cancer (LC) is the second most commonly diagnosed cancer among both men and women, and it stands as the leading cause of cancer-related mortality, characterized by high rates of morbidity and mortality. Among its subtypes, non-small cell lung cancer (NSCLC) is the most prevalent and one of the most challenging malignant tumors to treat. To date, various therapeutic approaches, including surgery, radiotherapy, and chemotherapy, have been employed in the management of lung cancer; however, due to its aggressive nature, the survival rates remain low. Consequently, exploring novel treatment strategies is of paramount importance. MicroRNAs (miRNAs), a large family of non-coding RNAs, play crucial roles in regulating several key biological processes, including cell proliferation, differentiation, inflammation, and apoptosis. Among these, microRNA155(miR-155) is one of the most conserved and versatile miRNAs, predominantly overexpressed in various diseases, including malignant tumors. This review elucidates the biological functions and roles of miR-155 in NSCLC and discusses its potential significance as a therapeutic target for future research directions and clinical applications.
Collapse
Affiliation(s)
- Xiangju Wei
- The First Clinical College, Xuzhou Medical University, Xuzhou, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xianmin Xiong
- The First Clinical College, Xuzhou Medical University, Xuzhou, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Ze Chen
- The First Clinical College, Xuzhou Medical University, Xuzhou, China
| | - Bi Chen
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Cantang Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Wenhui Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| |
Collapse
|
10
|
Al Subait A, Alghamdi RH, Ali R, Alsharidah A, Huwaizi S, Alkhodier RA, Almogren AS, Alzomia BA, Alaskar A, Boudjelal M. Discovery of PPAR Alpha Lipid Pathway Modulators That Do Not Bind Directly to the Receptor as Potential Anti-Cancer Compounds. Int J Mol Sci 2025; 26:736. [PMID: 39859448 PMCID: PMC11766124 DOI: 10.3390/ijms26020736] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 01/30/2025] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are considered good drug targets for breast cancer because of their involvement in fatty acid metabolism that induces cell proliferation. In this study, we used the KAIMRC1 breast cancer cell line. We showed that the PPARE-Luciferase reporter gets highly activated without adding any exogenous ligand when PPAR alpha is co-transfected, and the antagonist GW6471 can inhibit the activity. Using this reporter system, we screened 240 compounds representing kinase inhibitors, epigenetic modulators, and stem cell differentiators and identified compounds that inhibit the PPARα-activated PPARE-Luciferase reporter in the KAIMRC1 cell. We selected 11 compounds (five epigenetic modulators, two stem cell differentiators, and four kinase inhibitors) that inhibited the reporter by at least 40% compared to the controls (DMSO-treated cells). We tested them in a dose-dependent manner and measured the KAIMRC1 cell viability after 48 h. All 11 compounds induced the cell killing at different IC50 values. We selected two compounds, PHA665752 and NSC3852, to dissect how they kill KAIMRC1 cells compared to the antagonist GW6741. First, molecular docking and a TR-FRET PPARα binding assay showed that compared to GW6471, these two compounds could not bind to PPARα. This means they inhibit the PPARα pathway independently rather than binding to the receptor. We further confirmed that PHA665752 and NSC3852 induce cell killing depending on the level of PPARα expression, and as such, their potency for killing the SW620 colon cancer cell line that expresses the lowest level of PPARα was less potent than for the KAIMRC1 and MDA-MB-231 cell lines. Further, using an apoptosis array and fatty acid gene expression panel, we found that both compounds regulate the PPARα pathway by controlling the genes involved in the fatty acid oxidation process. Our findings suggest that these two compounds have opposite effects involving fatty acid oxidation in the KAIMRC1 breast cancer cell line. Although we do not fully understand their mechanism of action, our data provide new insights into the potential role of these compounds in targeting breast cancer cells.
Collapse
Affiliation(s)
- Arwa Al Subait
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia
| | - Raghad H. Alghamdi
- King Abdulaziz and His Companions Foundation for Giftedness and Creativity (MAWHIBA), Riyadh 11481, Saudi Arabia;
| | - Rizwan Ali
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
| | - Amani Alsharidah
- College of Science, King Saud University, Riyadh 11459, Saudi Arabia;
| | - Sarah Huwaizi
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
| | - Reem A. Alkhodier
- Department of Pharmaceutical Sciences, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia
| | - Aljawharah Saud Almogren
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
| | - Barrak A. Alzomia
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
| | - Ahmad Alaskar
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
| | - Mohamed Boudjelal
- Medical Research Core Facility and Platforms (MRCFP)-Drug Discovery Platform, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGHA), Riyadh 11481, Saudi Arabia; (A.A.S.)
| |
Collapse
|
11
|
Shen C, Suo Y, Guo J, Su W, Zhang Z, Yang S, Wu Z, Fan Z, Zhou X, Hu H. Development and validation of a glycolysis-associated gene signature for predicting the prognosis, immune landscape, and drug sensitivity in bladder cancer. Front Immunol 2025; 15:1430583. [PMID: 39867879 PMCID: PMC11757262 DOI: 10.3389/fimmu.2024.1430583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 12/16/2024] [Indexed: 01/28/2025] Open
Abstract
Background Bladder cancer (BCa) is one of the most common malignancies worldwide, and its prognostication and treatment remains challenging. The fast growth of various cancer cells requires reprogramming of its energy metabolism using aerobic glycolysis as a major energy source. However, the prognostic and therapeutic value of glycolysis-related genes in BCa remains to be determined. Methods The fused merge dateset from TCGA, GSE13507 and GSE31684 were used for the analysis of glycolysis-related genes expression or subtyping; and corresponding clinical data of these BCa patients were also collected. In the merge cohort, we constructed a 18 multigene signature using the least absolute shrinkage and selection operator (LASSO) Cox regression model. The four external cohorts (i.e., IMvigor210, GSE32894, GSE48276 and GSE48075) of BCa patients were used to validate the accuracy. We evaluated immune infiltration using seven published algorithms: CIBERSORT, QUANTISEQ, XCELL, TIMER, CIBERSORT-ABS, EPIC, and MCPCOUNTER. Subsequently, in order to analyze the correlation between risk groups(scores) and overall survival, recognised immunoregolatory cells or common chemotherapeutic agents, clinicopathological data and immune checkpoint-related genes of BCa patients, Wilcox rank test, chi-square test, cox regression and spearman's correlation were performed. Results Conspicuously, we could see that CD8+ T, cancer associated fibroblast, macrophage M2, NK, endothelial cells and so on were significantly dysregulated between the two risk groups. In addition, compared with the low-risk group, high-risk group predicted poor prognosis and relatively weak sensitivity of chemotherapy. Additionally, we also found that the expression level of partial genes in the model was significantly correlated with objective responses to anti-PD-1 or anti-PD-L1 treatment in the IMvigor210, GSE111636, GSE176307, GSE78220 or GSE67501 cohort; and its expression level was also varied in different objective response cases receiving tislelizumab combined with low-dose nab-paclitaxel therapy based on our mRNA sequencing (TRUCE-01). According to "GSEA" algorithm of R package "clusterProfiler", the most significantly enriched HALLMARK, KEGG pathway and GO term was separately the 'Epithelial Mesenchymal Transition', 'Ecm Receptor Interaction' and 'MF_Extracellular_matrix_structural_constitunet' in the high- vs. low-risk group. Subsequently, we verified the protein and mRNA expression of interested model-related genes from the Human Protein Atlas (HPA) and 10 paired BCa tissues collected by us. Furthermore, in vitro functional experiments demonstrated that FASN was a functional oncogene in BCa cells through promoting cell proliferation, migration, and invasion abilities. Conclusion In summary, the glycolysis-associated gene signature established by us exhibited a high predictive performance for the prognosis, immunotherapeutic responsiveness, and chemotherapeutic sensitivity of BCa. And, The model also might function as a chemotherapy and immune checkpoint inhibitor (ICI) treatment guidance.
Collapse
Affiliation(s)
- Chong Shen
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yong Suo
- Department of Urology, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Jian Guo
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Wei Su
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Department of Urology, The Characteristic Medical Center of Chinese People’s Armed Police Force, Tianjin, China
| | - Zhe Zhang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Shaobo Yang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Zhouliang Wu
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Zhenqian Fan
- Department of Endocrinology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xiaoliang Zhou
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Hailong Hu
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| |
Collapse
|
12
|
Geirnaert F, Kerkhove L, Montay-Gruel P, Gevaert T, Dufait I, De Ridder M. Exploring the Metabolic Impact of FLASH Radiotherapy. Cancers (Basel) 2025; 17:133. [PMID: 39796760 PMCID: PMC11720285 DOI: 10.3390/cancers17010133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 12/30/2024] [Accepted: 12/31/2024] [Indexed: 01/13/2025] Open
Abstract
FLASH radiotherapy (FLASH RT) is an innovative modality in cancer treatment that delivers ultrahigh dose rates (UHDRs), distinguishing it from conventional radiotherapy (CRT). FLASH RT has demonstrated the potential to enhance the therapeutic window by reducing radiation-induced damage to normal tissues while maintaining tumor control, a phenomenon termed the FLASH effect. Despite promising outcomes, the precise mechanisms underlying the FLASH effect remain elusive and are a focal point of current research. This review explores the metabolic and cellular responses to FLASH RT compared to CRT, with particular focus on the differential impacts on normal and tumor tissues. Key findings suggest that FLASH RT may mitigate damage in healthy tissues via altered reactive oxygen species (ROS) dynamics, which attenuate downstream oxidative damage. Studies indicate the FLASH RT influences iron metabolism and lipid peroxidation pathways differently than CRT. Additionally, various studies indicate that FLASH RT promotes the preservation of mitochondrial integrity and function, which helps maintain apoptotic pathways in normal tissues, attenuating damage. Current knowledge of the metabolic influences following FLASH RT highlights its potential to minimize toxicity in normal tissues, while also emphasizing the need for further studies in biologically relevant, complex systems to better understand its clinical potential. By targeting distinct metabolic pathways, FLASH RT could represent a transformative advance in RT, ultimately improving the therapeutic window for cancer treatment.
Collapse
Affiliation(s)
- Febe Geirnaert
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (F.G.); (L.K.); (T.G.); (I.D.)
| | - Lisa Kerkhove
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (F.G.); (L.K.); (T.G.); (I.D.)
| | - Pierre Montay-Gruel
- Radiation Oncology Department, Iridium Netwerk, 2610 Antwerp, Belgium;
- Antwerp Research in Radiation Oncology (AreRO), Center for Oncological Research (CORE), University of Antwerp, 2020 Antwerp, Belgium
| | - Thierry Gevaert
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (F.G.); (L.K.); (T.G.); (I.D.)
| | - Inès Dufait
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (F.G.); (L.K.); (T.G.); (I.D.)
| | - Mark De Ridder
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium; (F.G.); (L.K.); (T.G.); (I.D.)
| |
Collapse
|
13
|
Shi Q, Yang Z, Yang H, Xu L, Xia J, Gu J, Chen M, Wang Y, Zhao X, Liao Z, Mou Y, Gu X, Xie T, Sui X. Targeting ion channels: innovative approaches to combat cancer drug resistance. Theranostics 2025; 15:521-545. [PMID: 39744692 PMCID: PMC11671388 DOI: 10.7150/thno.103384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 10/21/2024] [Indexed: 01/11/2025] Open
Abstract
Ion channels, as functional molecules that regulate the flow of ions across cell membranes, have emerged as a promising target in cancer therapy due to their pivotal roles in cell proliferation, metastasis, apoptosis, drug resistance, and so on. Recently, increasing evidence suggests that dysregulation of ion channels is a common characteristic of cancer cells, contributing to their survival and the resistance to conventional therapies. For example, the aberrant expression of sodium (Na+) and potassium ion (K+) channels is significantly correlated with the sensitivity of chemotherapy drugs. The endogenous calcium (Ca2+) channels contribute to the acquired resistance of osimertinib in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer cell lines. Ferrous ions (Fe2+) enhance the sensitivity of breast cancer cells to doxorubicin treatment. Preclinical models have also demonstrated the effect of specific ion channel blockers or modulators on anticancer drug resistance. This review describes the current understanding about the interaction between ion channels and the therapeutic efficacy of anticancer drugs. Then, the therapeutic potential of ion channel blockers or modulators in enhancing the sensitivity or overcoming the resistance of cancer cells to anticancer therapies is discussed. Targeting ion channels will hopefully offer a novel and promising strategy for overcoming cancer drug resistance.
Collapse
Affiliation(s)
- Qian Shi
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Zijing Yang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Huan Yang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Lihui Xu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jing Xia
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jie Gu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Mengting Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yan Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xiaohong Zhao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Zehua Liao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yiping Mou
- General Surgery, Cancer Center, Department of Gastrointestinal-Pancreatic Surgery, Zhejiang Provincial People's Hospital, Hangzhou Medical University, Hangzhou, Zhejiang, China
| | - Xidong Gu
- Department of Breast Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xinbing Sui
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China
| |
Collapse
|
14
|
Singer M, Hamdy R, Elsayed TM, Husseiny MI. The Mechanisms and Therapeutic Implications of Metabolic Communication in the Tumor-Immune Microenvironment. METABOLIC DYNAMICS IN HOST-MICROBE INTERACTION 2025:291-315. [DOI: 10.1007/978-981-96-1305-2_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
|
15
|
Xiao H, Liu L, Huang S. STK32C modulates doxorubicin resistance in triple-negative breast cancer cells via glycolysis regulation. Mol Cell Biochem 2025; 480:459-471. [PMID: 38507019 DOI: 10.1007/s11010-024-04989-z] [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: 10/30/2023] [Accepted: 03/09/2024] [Indexed: 03/22/2024]
Abstract
Understanding the mechanisms underlying doxorubicin resistance in triple-negative breast cancer (TNBC) holds paramount clinical significance. In our study, we investigate the potential of STK32C, a little-explored kinase, to impact doxorubicin sensitivity in TNBC cells. Our findings reveal elevated STK32C expression in TNBC specimens, associated with unfavorable prognosis in doxorubicin-treated TNBC patients. Subsequent experiments highlighted that STK32C depletion significantly augmented the sensitivity of doxorubicin-resistant TNBC cells to doxorubicin. Mechanistically, we unveiled that the cytoplasmic subset of STK32C plays a pivotal role in mediating doxorubicin sensitivity, primarily through the regulation of glycolysis. Furthermore, the kinase activity of STK32C proved to be essential for its mediation of doxorubicin sensitivity, emphasizing its role as a kinase. Our study suggests that targeting STK32C may represent a novel therapeutic approach with the potential to improve doxorubicin's efficacy in TNBC treatment.
Collapse
Affiliation(s)
- Huawei Xiao
- Department of Medical Oncology, Yantaishan Hospital, Yantai, Shandong Province, China
| | - Lei Liu
- Department of Medical Oncology, Yantaishan Hospital, Yantai, Shandong Province, China
| | - Shaoyan Huang
- Department of Medical Oncology, Yantaishan Hospital, Yantai, Shandong Province, China.
| |
Collapse
|
16
|
Huang Y, Wu G, Bi G, Cheng L, Liang J, Li M, Zhang H, Shan G, Hu Z, Chen Z, Lin Z, Jiang W, Wang Q, Xi J, Yin S, Zhan C. Unveiling chemotherapy-induced immune landscape remodeling and metabolic reprogramming in lung adenocarcinoma by scRNA-sequencing. eLife 2024; 13:RP95988. [PMID: 39729352 DOI: 10.7554/elife.95988] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
Chemotherapy is widely used to treat lung adenocarcinoma (LUAD) patients comprehensively. Considering the limitations of chemotherapy due to drug resistance and other issues, it is crucial to explore the impact of chemotherapy and immunotherapy on these aspects. In this study, tumor samples from nine LUAD patients, of which four only received surgery and five received neoadjuvant chemotherapy, were subjected to scRNA-seq analysis. In vitro and in vivo assays, including flow cytometry, immunofluorescence, Seahorse assay, and tumor xenograft models, were carried out to validate our findings. A total of 83,622 cells were enrolled for subsequent analyses. The composition of cell types exhibited high heterogeneity across different groups. Functional enrichment analysis revealed that chemotherapy drove significant metabolic reprogramming in tumor cells and macrophages. We identified two subtypes of macrophages: Anti-mac cells (CD45+CD11b+CD86+) and Pro-mac cells (CD45+CD11b+ARG +) and sorted them by flow cytometry. The proportion of Pro-mac cells in LUAD tissues increased significantly after neoadjuvant chemotherapy. Pro-mac cells promote tumor growth and angiogenesis and also suppress tumor immunity. Moreover, by analyzing the remodeling of T and B cells induced by neoadjuvant therapy, we noted that chemotherapy ignited a relatively more robust immune cytotoxic response toward tumor cells. Our study demonstrates that chemotherapy induces metabolic reprogramming within the tumor microenvironment of LUAD, particularly affecting the function and composition of immune cells such as macrophages and T cells. We believe our findings will offer insight into the mechanisms of drug resistance and provide novel therapeutic targets for LUAD in the future.
Collapse
Affiliation(s)
- Yiwei Huang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Gujie Wu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guoshu Bi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lin Cheng
- Department of Pathology, Albert Einstein College of Medicine, Bronx, United States
| | - Jiaqi Liang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming Li
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Huan Zhang
- Department of Thoracic Surgery, Sichuan Cancer Hospital, University of Electronic Science and Technology of China, Sichuan, China
| | - Guangyao Shan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhengyang Hu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhencong Chen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zongwu Lin
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Jiang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qun Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Junjie Xi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shanye Yin
- Department of Pathology, Albert Einstein College of Medicine, Bronx, United States
| | - Cheng Zhan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
17
|
Maiti A, Mondal S, Choudhury S, Bandopadhyay A, Mukherjee S, Sikdar N. Oncometabolites in pancreatic cancer: Strategies and its implications. World J Exp Med 2024; 14:96005. [PMID: 39713078 PMCID: PMC11551704 DOI: 10.5493/wjem.v14.i4.96005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 08/24/2024] [Accepted: 09/14/2024] [Indexed: 10/31/2024] Open
Abstract
Pancreatic cancer (PanCa) is a catastrophic disease, being third lethal in both the genders around the globe. The possible reasons are extreme disease invasiveness, highly fibrotic and desmoplastic stroma, dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics. This inimitable tumor microenvironment (TME) or desmoplasia with excessive extracellular matrix accumulation, create an extremely hypovascular, hypoxic and nutrient-deficient zone inside the tumor. To survive, grow and proliferate in such tough TME, pancreatic tumor and stromal cells transform their metabolism. Transformed glucose, glutamine, fat, nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism, impart therapy resistance, and immunosuppression in PanCa. Thus, a finer knowledge of altered metabolism would uncover its metabolic susceptibilities. These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa. In this review, we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.
Collapse
Affiliation(s)
- Arunima Maiti
- Suraksha Diagnostics Pvt Ltd, Newtown, Rajarhat, Kolkata 700156, West Bengal, India
| | - Susmita Mondal
- Department of Zoology, Diamond Harbour Women’s University, Diamond Harbour 743368, West Bengal, India
| | - Sounetra Choudhury
- Human Genetics Unit, Indian Statistical Institute, Kolkata 700108, West Bengal, India
| | | | - Sanghamitra Mukherjee
- Department of Pathology, RG Kar Medical College and Hospital, Kolkata 700004, West Bengal, India
| | - Nilabja Sikdar
- Human Genetics Unit, Indian Statistical Institute, Kolkata 700108, West Bengal, India
- Scientist G, Estuarine and Coastal Studies Foundation, Howrah 711101, West Bengal, India
| |
Collapse
|
18
|
Wong D, Qiu H. New insights into the pharmacological inhibition of SRF activity: Key inhibitory targets and mechanisms. Vascul Pharmacol 2024; 157:107443. [PMID: 39586415 PMCID: PMC11648470 DOI: 10.1016/j.vph.2024.107443] [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: 10/28/2024] [Revised: 11/19/2024] [Accepted: 11/19/2024] [Indexed: 11/27/2024]
Abstract
Serum Response Factor (SRF) is a critical regulatory transcription factor widely expressed across cell types and is essential for animal survival. Excessive SRF activity has been linked to various pathological conditions and diseases, including cardiovascular diseases, cancers and neurodegenerative disorders, making the inhibition of SRF hyperactivity a promising therapeutic strategy. This review summarizes recent advancements in the discovery and development of SRF inhibitors, their regulatory mechanisms, and their respective molecular foundations. These insights deepen our understanding of current therapeutic potentials, paving the way for novel approaches to treat diseases associated with SRF hyperactivity.
Collapse
Affiliation(s)
- Daniel Wong
- Translational Cardiovascular Research Center, Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA.
| | - Hongyu Qiu
- Translational Cardiovascular Research Center, Department of Internal Medicine, College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85004, USA; Clinical Translational Sciences (CTS) and Bio5 Institution, University of Arizona, Tucson, AZ 8572, USA.
| |
Collapse
|
19
|
Cordani M, Michetti F, Zarrabi A, Zarepour A, Rumio C, Strippoli R, Marcucci F. The role of glycolysis in tumorigenesis: From biological aspects to therapeutic opportunities. Neoplasia 2024; 58:101076. [PMID: 39476482 PMCID: PMC11555605 DOI: 10.1016/j.neo.2024.101076] [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: 08/02/2024] [Revised: 10/13/2024] [Accepted: 10/17/2024] [Indexed: 11/11/2024]
Abstract
Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as "moonlighting" functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.
Collapse
Affiliation(s)
- Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid, Madrid 28040, Spain; Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid 28040, Spain
| | - Federica Michetti
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161, Italy; Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L., Spallanzani, IRCCS, Via Portuense, 292, Rome 00149, Italy
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Türkiye; Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan
| | - Atefeh Zarepour
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India
| | - Cristiano Rumio
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Trentacoste 2, Milan 20134, Italy
| | - Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome 00161, Italy; Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases L., Spallanzani, IRCCS, Via Portuense, 292, Rome 00149, Italy.
| | - Fabrizio Marcucci
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Trentacoste 2, Milan 20134, Italy.
| |
Collapse
|
20
|
He Y, Cai P, Hu A, Li J, Li X, Dang Y. The role of 1400 plasma metabolites in gastric cancer: A bidirectional Mendelian randomization study and metabolic pathway analysis. Medicine (Baltimore) 2024; 103:e40612. [PMID: 39612432 PMCID: PMC11608735 DOI: 10.1097/md.0000000000040612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 11/01/2024] [Indexed: 12/01/2024] Open
Abstract
While observational studies have illustrated correlations between plasma metabolites and gastric cancer (GC), the causal association between the 2 is still unclear. Our study aims to delineate the bidirectional relationship between plasma metabolites and GC and find potential metabolic pathways. We undertook a bidirectional 2-sample Mendelian randomization (MR) analysis to investigate the causal relationship, specificity, and direction of association between 1400 plasma metabolites and GC. The GWAS data for metabolites was obtained from a cohort of 8299 European individuals. And the GC's GWAS data was from FinnGen Consortium with 2384 European individuals, and the GWAS catalog with 1029 European ancestry cases for validation. Causal estimates were primarily calculated by the inverse-variance weighted (IVW) method. To ensure robustness, we performed comprehensive sensitivity analyses to assess heterogeneity and address concerns regarding horizontal pleiotropy. We validated the forward relationship between metabolites and GC from another database and implemented meta-analysis. Furthermore, we conducted metabolic enrichment and pathway analysis of these causal metabolites using MetaboAnalyst5.0/6.0 with the database of Kyoto Encyclopedia of Genes and Genomes. All statistical analysis was carried out using R software. Metabolites like 2s, 3R-dihydroxybutyrate, 4-acetamidobutanoate, ferulic acid 4-sulfate and methyl indole-3-acetate was proven positively linked with the development of GC. Asparagine, glucose to maltose ratio, glycohyocholate, Gulonate levels, linoleoyl ethanolamide and Spermidine to (N(1) + N(8))-acetylspermidine ratio was proven to be negatively associated with GC. Moreover, linoleic acid, histidine, glutamine, bilirubin, Succinate to proline ratio were found to be potentially linked to the development of GC. Furthermore, our analysis identified 18 significant metabolic pathways, including Arginine and proline metabolism (P < .009) and Valine, leucine, and isoleucine biosynthesis (P < .031). Our findings offer evidence supporting potential casual relations between multiple plasma metabolites and GC. These findings may offer great potential for future application of these biomarkers in GC screening and clinical prevention strategies.
Collapse
Affiliation(s)
- Yihao He
- Nanjing Medical University, Nanjing, China
| | | | - Anchi Hu
- Nanjing Medical University, Nanjing, China
| | - Jiali Li
- Nanjing Medical University, Nanjing, China
| | - Xuan Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yini Dang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| |
Collapse
|
21
|
Bauer L, Alkotub B, Ballmann M, Hasanzadeh Kafshgari M, Rammes G, Multhoff G. Cannabidiol (CBD) Protects Lung Endothelial Cells from Irradiation-Induced Oxidative Stress and Inflammation In Vitro and In Vivo. Cancers (Basel) 2024; 16:3589. [PMID: 39518030 PMCID: PMC11544820 DOI: 10.3390/cancers16213589] [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: 09/23/2024] [Revised: 10/14/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Objective: Radiotherapy, which is commonly used for the local control of thoracic cancers, also induces chronic inflammatory responses in the microvasculature of surrounding normal tissues such as the lung and heart that contribute to fatal radiation-induced lung diseases (RILDs) such as pneumonitis and fibrosis. In this study, we investigated the potential of cannabidiol (CBD) to attenuate the irradiation damage to the vasculature. Methods: We investigated the ability of CBD to protect a murine endothelial cell (EC) line (H5V) and primary lung ECs isolated from C57BL/6 mice from irradiation-induced damage in vitro and lung ECs (luECs) in vivo, by measuring the induction of oxidative stress, DNA damage, apoptosis (in vitro), and induction of inflammatory and pro-angiogenic markers (in vivo). Results: We demonstrated that a non-lethal dose of CBD reduces the irradiation-induced oxidative stress and early apoptosis of lung ECs by upregulating the expression of the cytoprotective mediator heme-oxygenase-1 (HO-1). The radiation-induced increased expression of inflammatory (ICAM-2, MCAM) and pro-angiogenic (VE-cadherin, Endoglin) markers was significantly reduced by a continuous daily treatment of C57BL/6 mice with CBD (i.p. 20 mg/kg body weight), 2 weeks before and 2 weeks after a partial irradiation of the lung (less than 20% of the lung volume) with 16 Gy. Conclusions: CBD has the potential to improve the clinical outcome of radiotherapy by reducing toxic side effects on the microvasculature of the lung.
Collapse
Affiliation(s)
- Lisa Bauer
- Department of Radiation Oncology, TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany;
- Radiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany;
| | - Bayan Alkotub
- Institute of Biological and Medical Imaging (IBMI), Helmholtz Zentrum München (HMGU), 85764 Neuherberg, Germany;
- Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany
| | - Markus Ballmann
- Department of Anesthesiology and Intensive Care Medicine, TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany; (M.B.); (G.R.)
| | - Morteza Hasanzadeh Kafshgari
- Radiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany;
| | - Gerhard Rammes
- Department of Anesthesiology and Intensive Care Medicine, TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany; (M.B.); (G.R.)
| | - Gabriele Multhoff
- Department of Radiation Oncology, TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany;
- Radiation Immuno-Oncology Group, Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, University Hospital of the Technical University of Munich (TUM), 81675 Munich, Germany;
| |
Collapse
|
22
|
Khan A, Rehman AU, Siddiqui S, Khan J, Massey S, Singh P, Saluja D, Husain SA, Iqbal MA. Withaferin A decreases glycolytic reprogramming in breast cancer. Sci Rep 2024; 14:23147. [PMID: 39366987 PMCID: PMC11452501 DOI: 10.1038/s41598-024-72221-5] [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: 03/21/2023] [Accepted: 09/04/2024] [Indexed: 10/06/2024] Open
Abstract
Reprogrammed glucose metabolism is considered as the hallmark of cancer with therapeutic implications. Phytocompounds have potential to inhibit cancer metabolism. Here, we tested the ability of Withaferin A (WA), a withanolide derived from Withania somnifera, in modulating cancer metabolism. The assessed effect of WA on aerobic glycolysis in breast cancer cell lines showed that WA decreases the glucose uptake, lactate production and ATP generation by inhibiting the expression of key glycolytic enzymes i.e., GLUT1, HK2 and PKM2. We also identified that WA induced inhibition of cancer glycolysis by targeting c-myc as validated by silencing experiments followed by metabolic readouts. Decreased glycolysis resulted in reduced cell viability, biomass and colony forming ability of breast cancer cells. To further validate our in vitro findings in breast cancer patients, we analyzed 90 metabolic pathways in ~ 2000 breast tumors and observed that glycolysis is the most deregulated pathway in breast tumors. Deregulated glycolysis also predicted poor prognosis in breast cancer patients. In addition, patient data showed correlation between c-myc expression and glycolytic deregulation in breast cancer. Taken together, our results highlight the role of WA in inhibiting breast cancer metabolism via c-myc/glycolysis axis.
Collapse
Affiliation(s)
- Asifa Khan
- Department of Biosciences, Jamia Millia Islamia (A Central University), New Delhi, 110025, India
| | - Asad Ur Rehman
- Medical Biotechnology Laboratory, Dr B R Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, India
| | - Shumaila Siddiqui
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India
| | - Jiyauddin Khan
- Medical Biotechnology Laboratory, Dr B R Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, India
| | - Sheersh Massey
- Department of Biosciences, Jamia Millia Islamia (A Central University), New Delhi, 110025, India
| | - Prithvi Singh
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia (A Central University), New Delhi, 110025, India
| | - Daman Saluja
- Medical Biotechnology Laboratory, Dr B R Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, India
| | - Syed Akhtar Husain
- Department of Biosciences, Jamia Millia Islamia (A Central University), New Delhi, 110025, India.
| | - Mohammad Askandar Iqbal
- Department of Biotechnology, Jamia Millia Islamia (A Central University), New Delhi, 110025, India.
- Thumbay Research Institute for Precision Medicine (TRIPM), College of Medicine, Gulf Medical University, Ajman, United Arab Emirates.
| |
Collapse
|
23
|
de la Harpe A, Beukes N, Frost C. Mitochondrial calcium overload contributes to cannabinoid-induced paraptosis in hormone-responsive breast cancer cells. Cell Prolif 2024; 57:e13650. [PMID: 38721827 PMCID: PMC11471428 DOI: 10.1111/cpr.13650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 03/22/2024] [Accepted: 04/15/2024] [Indexed: 10/15/2024] Open
Abstract
Studies have shown that natural products can induce paraptosis in tumour cell lines. Paraptosis is characterized by cytoplasmic vacuolation arising from the endoplasmic reticulum (ER) and mitochondria. The mechanism of paraptosis is unclear; however, dysregulation of Ca2+ homeostasis is believed to affect paraptosis induction. This study investigated the mechanism of cell death induced by a phytocannabinoid ratio in the MCF7 breast cancer cell line. The crystal violet assay was used to detect changes in viability and morphology changes were investigated using light and transmission electron microscopy. Various inhibitors, fluorescent staining with high-content screening, and Western blot analysis were used to investigate different cell death mechanisms. The phytocannabinoid ratio induced significant cell death and cytoplasmic vacuolation in MCF7 cells; however, no apoptosis, necrosis, autophagy, or ferroptosis was detected. Vacuolation induced by phytocannabinoid treatment was inhibited by cycloheximide, suggesting paraptosis induction. The mechanism of paraptosis induction was investigated, and it was found that treatment (1) induced ER dilation and mitochondrial swelling, (2) induced significant ER stress and mitochondrial Ca2+ overload and dysfunction, which appeared to be mediated by the voltage-dependent anion channel, and (3) significantly impaired all mitochondrial metabolic pathways. The data demonstrated that paraptosis induced by the cannabinoid ratio was mediated by Ca2+ flux from the ER to the mitochondria. These findings highlight a novel mechanism of cannabinoid-induced cell death and emphasize the anti-cancer potential of cannabinoid ratios, which exhibited enhanced effects compared to individual cannabinoids.
Collapse
Affiliation(s)
- A. de la Harpe
- Department of Biochemistry and MicrobiologyNelson Mandela UniversityPort ElizabethSouth Africa
| | - N. Beukes
- Department of Biochemistry and MicrobiologyNelson Mandela UniversityPort ElizabethSouth Africa
| | - C. Frost
- Department of Biochemistry and MicrobiologyNelson Mandela UniversityPort ElizabethSouth Africa
| |
Collapse
|
24
|
Tufail M, Jiang CH, Li N. Altered metabolism in cancer: insights into energy pathways and therapeutic targets. Mol Cancer 2024; 23:203. [PMID: 39294640 PMCID: PMC11409553 DOI: 10.1186/s12943-024-02119-3] [Citation(s) in RCA: 68] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 09/09/2024] [Indexed: 09/21/2024] Open
Abstract
Cancer cells undergo significant metabolic reprogramming to support their rapid growth and survival. This study examines important metabolic pathways like glycolysis, oxidative phosphorylation, glutaminolysis, and lipid metabolism, focusing on how they are regulated and their contributions to the development of tumors. The interplay between oncogenes, tumor suppressors, epigenetic modifications, and the tumor microenvironment in modulating these pathways is examined. Furthermore, we discuss the therapeutic potential of targeting cancer metabolism, presenting inhibitors of glycolysis, glutaminolysis, the TCA cycle, fatty acid oxidation, LDH, and glucose transport, alongside emerging strategies targeting oxidative phosphorylation and lipid synthesis. Despite the promise, challenges such as metabolic plasticity and the need for combination therapies and robust biomarkers persist, underscoring the necessity for continued research in this dynamic field.
Collapse
Affiliation(s)
- Muhammad Tufail
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Can-Hua Jiang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Precancerous Lesions, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ning Li
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
- Institute of Oral Precancerous Lesions, Central South University, Changsha, China.
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
| |
Collapse
|
25
|
Carrà G, Petiti J, Tolino F, Vacca R, Orso F. MicroRNAs in metabolism for precision treatment of lung cancer. Cell Mol Biol Lett 2024; 29:121. [PMID: 39256662 PMCID: PMC11384722 DOI: 10.1186/s11658-024-00632-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 08/12/2024] [Indexed: 09/12/2024] Open
Abstract
The dysregulation of miRNAs in lung cancer has been extensively documented, with specific miRNAs acting as both tumor suppressors and oncogenes, depending on their target genes. Recent research has unveiled the regulatory roles of miRNAs in key metabolic pathways, such as glycolysis, the tricarboxylic acid cycle, fatty acid metabolism, and autophagy, which collectively contribute to the aberrant energy metabolism characteristic of cancer cells. Furthermore, miRNAs are increasingly recognized as critical modulators of the tumor microenvironment, impacting immune response and angiogenesis. This review embarks on a comprehensive journey into the world of miRNAs, unraveling their multifaceted roles, and more notably, their emerging significance in the context of cancer, with a particular focus on lung cancer. As we navigate this extensive terrain, we will explore the fascinating realm of miRNA-mediated metabolic rewiring, a phenomenon that plays a pivotal role in the progression of lung cancer and holds promise in the development of novel therapeutic strategies.
Collapse
Affiliation(s)
- Giovanna Carrà
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
- San Luigi Gonzaga Hospital, Orbassano, Italy.
| | - Jessica Petiti
- Division of Advanced Materials Metrology and Life Sciences, Istituto Nazionale di Ricerca Metrologica (INRiM), 10135, Turin, Italy
| | - Federico Tolino
- Department of Translational Medicine (DIMET), University of Eastern Piedmont, Novara, Italy
| | - Rita Vacca
- Molecular Biotechnology Center "Guido Tarone", University of Torino, Turin, Italy
| | - Francesca Orso
- Department of Translational Medicine (DIMET), University of Eastern Piedmont, Novara, Italy.
| |
Collapse
|
26
|
El-Tanani M, Rabbani SA, El-Tanani Y, Matalka II. Metabolic vulnerabilities in cancer: A new therapeutic strategy. Crit Rev Oncol Hematol 2024; 201:104438. [PMID: 38977145 DOI: 10.1016/j.critrevonc.2024.104438] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 07/02/2024] [Indexed: 07/10/2024] Open
Abstract
Cancer metabolism is now a key area for therapeutic intervention, targeting unique metabolic reprogramming crucial for tumor growth and survival. This article reviews the therapeutic potential of addressing metabolic vulnerabilities through glycolysis and glutaminase inhibitors, which disrupt cancer cell metabolism. Challenges such as tumor heterogeneity and adaptive resistance are discussed, with strategies including personalized medicine and predictive biomarkers to enhance treatment efficacy. Additionally, integrating diet and lifestyle changes with metabolic targeting underscores a holistic approach to improving therapy outcomes. The article also examines the benefits of incorporating these strategies into standard care, highlighting the potential for more tailored, safer treatments. In conclusion, exploiting metabolic vulnerabilities promises a new era in oncology, positioning metabolic targeting at the forefront of personalized cancer therapy and transforming patient care.
Collapse
Affiliation(s)
- Mohamed El-Tanani
- RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates.
| | - Syed Arman Rabbani
- RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates.
| | - Yahia El-Tanani
- Medical School, St George's University of London, Cranmer Terrace, Tooting, London, UK
| | - Ismail I Matalka
- RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates; Department of Pathology and Microbiology, Medicine, Jordan University of Science and Technology, Irbid, Jordan.
| |
Collapse
|
27
|
Vanthienen W, Fernández-García J, Baietti MF, Claeys E, Van Leemputte F, Nguyen L, Goossens V, Deparis Q, Broekaert D, Vlayen S, Audenaert D, Delforge M, D'Amuri A, Van Zeebroeck G, Leucci E, Fendt SM, Thevelein JM. The novel family of Warbicin ® compounds inhibits glucose uptake both in yeast and human cells and restrains cancer cell proliferation. Front Oncol 2024; 14:1411983. [PMID: 39239276 PMCID: PMC11374660 DOI: 10.3389/fonc.2024.1411983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 07/29/2024] [Indexed: 09/07/2024] Open
Abstract
Many cancer cells share with yeast a preference for fermentation over respiration, which is associated with overactive glucose uptake and breakdown, a phenomenon called the Warburg effect in cancer cells. The yeast tps1Δ mutant shows even more pronounced hyperactive glucose uptake and phosphorylation causing glycolysis to stall at GAPDH, initiation of apoptosis through overactivation of Ras and absence of growth on glucose. The goal of the present work was to use the yeast tps1Δ strain to screen for novel compounds that would preferentially inhibit overactive glucose influx into glycolysis, while maintaining basal glucose catabolism. This is based on the assumption that the overactive glucose catabolism of the tps1Δ strain might have a similar molecular cause as the Warburg effect in cancer cells. We have isolated Warbicin ® A as a compound restoring growth on glucose of the yeast tps1Δ mutant, showed that it inhibits the proliferation of cancer cells and isolated structural analogs by screening directly for cancer cell inhibition. The Warbicin ® compounds are the first drugs that inhibit glucose uptake by both yeast Hxt and mammalian GLUT carriers. Specific concentrations did not evoke any major toxicity in mice but increase the amount of adipose tissue likely due to reduced systemic glucose uptake. Surprisingly, Warbicin ® A inhibition of yeast sugar uptake depends on sugar phosphorylation, suggesting transport-associated phosphorylation as a target. In vivo and in vitro evidence confirms physical interaction between yeast Hxt7 and hexokinase. We suggest that reversible transport-associated phosphorylation by hexokinase controls the rate of glucose uptake through hydrolysis of the inhibitory ATP molecule in the cytosolic domain of glucose carriers and that in yeast tps1Δ cells and cancer cells reversibility is compromised, causing constitutively hyperactive glucose uptake and phosphorylation. Based on their chemical structure and properties, we suggest that Warbicin ® compounds replace the inhibitory ATP molecule in the cytosolic domain of the glucose carriers, preventing hexokinase to cause hyperactive glucose uptake and catabolism.
Collapse
Affiliation(s)
- Ward Vanthienen
- Center for Microbiology, VIB, Leuven-Heverlee, Belgium
- Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven, Leuven-Heverlee, Belgium
| | - Juan Fernández-García
- VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Maria Francesca Baietti
- TRACE PDX Platform, Laboratory of RNA Cancer Biology, LKI Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - Elisa Claeys
- TRACE PDX Platform, Laboratory of RNA Cancer Biology, LKI Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - Frederik Van Leemputte
- Center for Microbiology, VIB, Leuven-Heverlee, Belgium
- Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven, Leuven-Heverlee, Belgium
| | - Long Nguyen
- Screening Core, VIB, Ghent, Belgium
- Centre for Bioassay Development and Screening (C-BIOS), Ghent University, Ghent, Belgium
| | - Vera Goossens
- Screening Core, VIB, Ghent, Belgium
- Centre for Bioassay Development and Screening (C-BIOS), Ghent University, Ghent, Belgium
| | - Quinten Deparis
- Center for Microbiology, VIB, Leuven-Heverlee, Belgium
- Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven, Leuven-Heverlee, Belgium
| | - Dorien Broekaert
- VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Sophie Vlayen
- LKI Leuven Cancer Institute Leuven, KU Leuven, Leuven, Belgium
| | - Dominique Audenaert
- Screening Core, VIB, Ghent, Belgium
- Centre for Bioassay Development and Screening (C-BIOS), Ghent University, Ghent, Belgium
| | - Michel Delforge
- LKI Leuven Cancer Institute Leuven, KU Leuven, Leuven, Belgium
| | | | - Griet Van Zeebroeck
- Center for Microbiology, VIB, Leuven-Heverlee, Belgium
- Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven, Leuven-Heverlee, Belgium
| | - Eleonora Leucci
- TRACE PDX Platform, Laboratory of RNA Cancer Biology, LKI Leuven Cancer Institute, KU Leuven, Leuven, Belgium
| | - Sarah-Maria Fendt
- VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Johan M Thevelein
- Center for Microbiology, VIB, Leuven-Heverlee, Belgium
- Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven, Leuven-Heverlee, Belgium
- NovelYeast bv, Bio-Incubator, BIO4, Leuven-Heverlee, Belgium
| |
Collapse
|
28
|
Wu X, Chen H, Ge Z, Luo B, Pan H, Shen Y, Xie Z, Zhou C. A novel mitochondria-related algorithm for predicting the survival outcomes and drug sensitivity of patients with lung adenocarcinoma. Front Mol Biosci 2024; 11:1397281. [PMID: 39184152 PMCID: PMC11342398 DOI: 10.3389/fmolb.2024.1397281] [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: 03/08/2024] [Accepted: 07/26/2024] [Indexed: 08/27/2024] Open
Abstract
Background Mitochondria have always been considered too be closely related to the occurrence and development of malignant tumors. However, the bioinformatic analysis of mitochondria in lung adenocarcinoma (LUAD) has not been reported yet. Methods In the present study, we constructed a novel and reliable algorithm, comprising a consensus cluster analysis and risk assessment model, to predict the survival outcomes and tumor immunity for patients with terminal LUAD. Results Patients with LUAD were classified into three clusters, and patients in cluster 1 exhibited the best survival outcomes. The patients in cluster 3 had the highest expression of PDL1 (encoding programmed cell death 1 ligand 11) and HAVCR2 (encoding Hepatitis A virus cellular receptor 2), and the highest tumor mutation burden (TMB). In the risk assessment model, patients in the low-risk group tended to have a significantly better survival outcome. Furthermore, the risk score combined with stage could act as a reliable independent prognostic indicator for patients with LUAD. The prognostic signature is a novel and effective biomarker to select anti-tumor drugs. Low-risk patients tended to have a higher expression of CTLA4 (encoding cytotoxic T-lymphocyte associated protein 4) and HAVCR2. Moreover, patients in the high-risk group were more sensitive to Cisplatin, Docetaxel, Erlotinib, Gemcitabine, and Paclitaxel, while low-risk patients would probably benefit more from Gefitinib. Conclusion We constructed a novel and reliable algorithm comprising a consensus cluster analysis and risk assessment model to predict survival outcomes, which functions as a reliable guideline for anti-tumor drug treatment for patients with terminal LUAD.
Collapse
Affiliation(s)
- Xianqiao Wu
- Department of Thoracic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Hang Chen
- Department of Thoracic Surgery, Ningbo Medical Center LiHuiLi Hospital, Ningbo, Zhejiang, China
| | - Zhen Ge
- Department of Thoracic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Binyu Luo
- Department of Thoracic Surgery, Ningbo Medical Center LiHuiLi Hospital, Ningbo, Zhejiang, China
| | - Hanbo Pan
- Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiming Shen
- Department of Otology and Skull Base Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
| | - Zuorun Xie
- Department of Thoracic Surgery, Ningbo Medical Center LiHuiLi Hospital, Ningbo, Zhejiang, China
| | - Chengwei Zhou
- Department of Thoracic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| |
Collapse
|
29
|
Duenas-Gonzalez A, Gonzalez-Fierro A, Bornstein-Quevedo L, Gutierrez-Delgado F, Kast RE, Chavez-Blanco A, Dominguez-Gomez G, Candelaria M, Romo-Pérez A, Correa-Basurto J, Lizano M, Perez-de la Cruz V, Robles-Bañuelos B, Nuñez-Corona D, Martinez-Perez E, Verastegui E. Multitargeted polypharmacotherapy for cancer treatment. theoretical concepts and proposals. Expert Rev Anticancer Ther 2024; 24:665-677. [PMID: 38913911 DOI: 10.1080/14737140.2024.2372336] [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: 01/26/2024] [Accepted: 06/21/2024] [Indexed: 06/26/2024]
Abstract
INTRODUCTION The pharmacological treatment of cancer has evolved from cytotoxic to molecular targeted therapy. The median survival gains of 124 drugs approved by the FDA from 2003 to 2021 is 2.8 months. Targeted therapy is based on the somatic mutation theory, which has some paradoxes and limitations. While efforts of targeted therapy must continue, we must study newer approaches that could advance therapy and affordability for patients. AREAS COVERED This work briefly overviews how cancer therapy has evolved from cytotoxic chemotherapy to current molecular-targeted therapy. The limitations of the one-target, one-drug approach considering cancer as a robust system and the basis for multitargeting approach with polypharmacotherapy using repurposing drugs. EXPERT OPINION Multitargeted polypharmacotherapy for cancer with repurposed drugs should be systematically investigated in preclinical and clinical studies. Remarkably, most of these proposed drugs already have a long history in the clinical setting, and their safety is known. In principle, the risk of their simultaneous administration should not be greater than that of a first-in-human phase I study as long as the protocol is developed with strict vigilance to detect early possible side effects from their potential interactions. Research on cancer therapy should go beyond the prevailing paradigm targeted therapy.
Collapse
Affiliation(s)
- Alfonso Duenas-Gonzalez
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas UNAM, Mexico City, Mexico
- Subdireccion de Investigación Básica, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Aurora Gonzalez-Fierro
- Subdireccion de Investigación Básica, Instituto Nacional de Cancerología, Mexico City, Mexico
| | | | - Francisco Gutierrez-Delgado
- Centro de Estudios y Prevención del Cancer Tuxtla Gutiérrez, Chiapas, México; Latin American School of Oncology (ELO), México City, Mexico
| | - Richard E Kast
- Head of Faculty, Brain Study, IIAIG Study Center, Burlington, VT, USA
| | - Alma Chavez-Blanco
- Subdireccion de Investigación Básica, Instituto Nacional de Cancerología, Mexico City, Mexico
| | | | - Myrna Candelaria
- Departamento de Hematología, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Adriana Romo-Pérez
- Instituto de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Jose Correa-Basurto
- Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, SEPI-ESM, Instituto Politécnico Nacional, México, Mexico City, Mexico
| | - Marcela Lizano
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas UNAM, Mexico City, Mexico
- Subdireccion de Investigación Básica, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Veronica Perez-de la Cruz
- Neurobiochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez", Mexico City, Mexico
| | | | - David Nuñez-Corona
- Subdireccion de Investigación Básica, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Erandi Martinez-Perez
- Subdireccion de Investigación Básica, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Emma Verastegui
- Departamento de Cuidados Paliativos, Division de Cirugia, Instituto Nacional de Cancerologia, Mexico City, Mexico
| |
Collapse
|
30
|
Satapathi D, Das M, Das UK, Laha S, Kundu P, Choudhuri I, Bhattacharya N, Samanta BC, Chattopadhyay N, Maity T. Experimental and molecular modelling demonstration of effective DNA and protein binding as well as anticancer potential of two mononuclear Cu(II) and Co(II) complexes with isothiocyanate and azide as anionic residues. Int J Biol Macromol 2024; 275:133716. [PMID: 38977049 DOI: 10.1016/j.ijbiomac.2024.133716] [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: 03/27/2024] [Revised: 07/03/2024] [Accepted: 07/05/2024] [Indexed: 07/10/2024]
Abstract
In the present study, one mononuclear Cu(II) [CuL(SCN)] (1) and one mononuclear Co(II) [CoLN3] (2) complexes, with a Schiff base ligand (HL) formed by condensation of 2-picolylamine and salicylaldehyde, have been successfully developed and structurally characterized. The square planer geometry of both complexes is fulfilled by the coordination of one deprotonated ligand and one ancillary ligand SCN-(1) or N3-(2) to the metal centre. Binding affinities of both complexes with deoxyribonucleic acid (DNA) and human serum albumin (HSA) are investigated using several biophysical and spectroscopic techniques. High values of the macromolecule-complex binding constants and other results confirm the effectiveness of both complexes towards binding with DNA and HSA. The determined values of the thermodynamic parameters support spontaneous interactions of both complexes with HSA, while fluorescence displacement and DNA melting studies establish groove-binding interactions with DNA for both complexes 1 and 2. The molecular modelling study validates the experimental findings. Both complexes are subjected to an MTT test establishing the anticancer property of complex 1 with lower risk to normal cells, confirmed by the IC50 values of the complex for HeLa cancer cells and HEK normal cells. Finally, a nuclear staining analysis reveals that the complexes have caused apoptotic cell death.
Collapse
Affiliation(s)
- Dibyendu Satapathi
- Department of Chemistry, Prabhat Kumar College, Purba Medinipur, Contai, West Bengal 721404, India
| | - Manik Das
- Department of Chemistry, Prabhat Kumar College, Purba Medinipur, Contai, West Bengal 721404, India
| | - Uttam Kumar Das
- Department of Chemistry, School of Physical Science, Mahatma Gandhi Central University, Bihar, India
| | - Soumik Laha
- Indian Institute of Chemical Biology, Jadavpur, Kolkata, West Bengal, India
| | - Pronab Kundu
- Department of Chemistry, Presidency University, Yelahanka, Bengaluru 560064, India
| | - Indranil Choudhuri
- Department of Biotechnology, Panskura Banamali College, Panskura, West Bengal, India
| | - Nandan Bhattacharya
- Department of Biotechnology, Panskura Banamali College, Panskura, West Bengal, India
| | | | | | - Tithi Maity
- Department of Chemistry, Prabhat Kumar College, Purba Medinipur, Contai, West Bengal 721404, India.
| |
Collapse
|
31
|
Wu G, Liu J, Shi H, Pan B, Li M, Wang X, Li Y, Cheng L, Guo W, Huang Y. The associations between dysregulation of human blood metabolites and lung cancer risk: evidence from genetic data. BMC Cancer 2024; 24:854. [PMID: 39026146 PMCID: PMC11256634 DOI: 10.1186/s12885-024-12416-1] [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: 03/04/2024] [Accepted: 05/22/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Metabolic dysregulation is recognized as a significant hallmark of cancer progression. Although numerous studies have linked specific metabolic pathways to cancer incidence, the causal relationship between blood metabolites and lung cancer risk remains unclear. METHODS Genomic data from 29,266 lung cancer patients and 56,450 control individuals from the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium (TRICL-ILCCO) were utilized, and findings were replicated using additional data from the FinnGen consortium. The analysis focused on the associations between 486 blood metabolites and the susceptibility to overall lung cancer and its three major clinical subtypes. Various Mendelian randomization methods, including inverse-variance weighting, weighted median estimation, and MR-Egger regression, were employed to ensure the robustness of our findings. RESULTS A total of 19 blood metabolites were identified with significant associations with lung cancer risk. Specifically, oleate (OR per SD = 2.56, 95% CI: 1.51 to 4.36), 1-arachidonoylglyceropholine (OR = 1.79, 95% CI: 1.22 to 2.65), and arachidonate (OR = 1.67, 95% CI: 1.16 to 2.40) were associated with a higher risk of lung cancer. Conversely, 1-linoleoylglycerophosphoethanolamine (OR = 0.57, 95% CI: 0.40 to 0.82), ADpSGEGDFXAEGGGVR, a fibrinogen cleavage peptide (OR = 0.60, 95% CI: 0.47 to 0.77), and isovalerylcarnitine (OR = 0.62, 95% CI: 0.49 to 0.78) were associated with a lower risk of lung cancer. Notably, isoleucine (OR = 9.64, 95% CI: 2.55 to 36.38) was associated with a significantly higher risk of lung squamous cell cancer, while acetyl phosphate (OR = 0.11, 95% CI: 0.01 to 0.89) was associated with a significantly lower risk of small cell lung cancer. CONCLUSION This study reveals the complex relationships between specific blood metabolites and lung cancer risk, highlighting their potential as biomarkers for lung cancer prevention, screening, and treatment. The findings not only deepen our understanding of the metabolic mechanisms of lung cancer but also provide new insights for future treatment strategies.
Collapse
Affiliation(s)
- Gujie Wu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jun Liu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Haochun Shi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Binyang Pan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Min Li
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiaolin Wang
- Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yao Li
- Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Lin Cheng
- Regenerative Medicine Institute, Biomedical Sciences Building, School of Medicine, National University of Ireland (NUI), Galway, Ireland.
| | - Weigang Guo
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Yiwei Huang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| |
Collapse
|
32
|
Wu B, Pan F, Wang Q, Liang Q, Qiu H, Zhou S, Zhou X. Association between blood metabolites and basal cell carcinoma risk: a two-sample Mendelian randomization study. Front Endocrinol (Lausanne) 2024; 15:1413777. [PMID: 39045268 PMCID: PMC11263015 DOI: 10.3389/fendo.2024.1413777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 06/24/2024] [Indexed: 07/25/2024] Open
Abstract
Background Circulating metabolites, which play a crucial role in our health, have been reported to be disordered in basal cell carcinoma (BCC). Despite these findings, evidence is still lacking to determine whether these metabolites directly promote or prevent BCC's progression. Therefore, our study aims to examine the potential effects of circulating metabolites on BCC progression. Material and methods We conducted a two-sample Mendelian randomization (MR) analysis using data from two separate genome-wide association studies (GWAS). The primary study included data for 123 blood metabolites from a GWAS with 25,000 Finnish individuals, while the secondary study had data for 249 blood metabolites from a GWAS with 114,000 UK Biobank participants.GWAS data for BCC were obtained from the UK Biobank for the primary analysis and the FinnGen consortium for the secondary analysis. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. Results In the primary analysis, significant causal relationships were found between six metabolic traits and BCC with the inverse variance weighted (IVW) method after multiple testing [P < 4 × 10-4 (0.05/123)]. Four metabolic traits were discovered to be significantly linked with BCC in the secondary analysis, with a significance level of P < 2 × 10-4 (0.05/249). We found that all the significant traits are linked to Polyunsaturated Fatty Acids (PUFAs) and their degree of unsaturation. Conclusion Our research has revealed a direct link between the susceptibility of BCC and Polyunsaturated Fatty Acids and their degree of unsaturation. This discovery implies screening and prevention of BCC.
Collapse
Affiliation(s)
- Bingliang Wu
- Department of Medical Cosmetology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - FuQiang Pan
- Department of Medical Cosmetology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - QiaoQi Wang
- Department of Health Examination Center, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qian Liang
- Department of Medical Cosmetology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - HouHuang Qiu
- Department of Medical Cosmetology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - SiYuan Zhou
- Department of Medical Cosmetology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiang Zhou
- Department of Medical Cosmetology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| |
Collapse
|
33
|
Meng J, Yang B, Shu C, Jiang S. Saikosaponin-d mediates FOXG1 to reverse docetaxel resistance in prostate cancer through oxidative phosphorylation. Mutat Res 2024; 829:111875. [PMID: 39098234 DOI: 10.1016/j.mrfmmm.2024.111875] [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: 04/19/2024] [Revised: 06/19/2024] [Accepted: 07/22/2024] [Indexed: 08/06/2024]
Abstract
BACKGROUND Prostate cancer (PCa), a prevalent malignancy worldwide, is frequently identified in advanced stages due to the absence of distinctive early symptoms, thereby culminating in the development of chemotherapy-induced drug resistance. Exploring novel resistance mechanisms and identifying new therapeutic agents can facilitate the advancement of more efficacious strategies for PCa treatment. METHODS Bioinformatics analysis was employed to investigate the expression of FOXG1 in PCa tissues. Subsequently, qRT-PCR was utilized to validate FOXG1 mRNA expression levels in corresponding PCa cell lines. FOXG1 knockdown was performed, and cell proliferation was assessed using CCK-8 assays, while cell migration and invasion capabilities were evaluated through wound healing and Transwell assays. Western blot and Seahorse analyzer were used to measure oxidative phosphorylation (OXPHOS) levels. Additionally, to explore potential approaches to alleviate PCa drug resistance, this study assessed the impact of biologically active saikosaponin-d (SSd) on PCa malignant progression and resistance by regulating FOXG1 expression. RESULTS FOXG1 exhibited high expression in PCa tissues and cell lines. Knockdown of FOXG1 inhibited the proliferation, migration, and invasion of PCa cells, while FOXG1 overexpression had the opposite effect and promoted OXPHOS levels. The addition of an OXPHOS inhibitor prevented this outcome. Finally, SSd was shown to suppress FOXG1 expression and reverse docetaxel resistance in PCa cells through the OXPHOS pathway. CONCLUSION This work demonstrated that SSd mediated FOXG1 to reverse malignant progression and docetaxel resistance in PCa through OXPHOS.
Collapse
Affiliation(s)
- Jun Meng
- Department of Urology, Wusong Central Hospital, Shanghai 200940, China
| | - Bo Yang
- Department of Urology, Wusong Central Hospital, Shanghai 200940, China
| | - Chang Shu
- Department of Urology, Wusong Central Hospital, Shanghai 200940, China
| | - Shuai Jiang
- Department of Urology, Wusong Central Hospital, Shanghai 200940, China.
| |
Collapse
|
34
|
Luís C, Fernandes R, Soares R. Exploring variations in glycolytic and gluconeogenic enzymes and isoforms across breast cancer cell lines and tissues. Carbohydr Res 2024; 541:109169. [PMID: 38838492 DOI: 10.1016/j.carres.2024.109169] [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: 12/07/2023] [Revised: 05/07/2024] [Accepted: 05/29/2024] [Indexed: 06/07/2024]
Abstract
It is well established that tumour cells undergo metabolic changes to acquire biological advantage over normal cells with activation of the glycolytic pathway, a process termed "Warburg effect". Enzyme isoforms are alternative enzymatic forms with the same function but with different biochemical or epigenetic features. Moreover, isoforms may have varying impacts on different metabolic pathways. We challenge ourselves to analyse the glycolytic and gluconeogenic enzymes and isoforms in breast cancer, a complex and heterogeneous pathology, associated with high incidence and mortality rates especially among women. We analysed epithelial and tumour cell lines by RT-PCR and compared values to a publicly available database for the expression profile of normal and tumour tissues (Gepia) of enzymes and enzymatic isoforms from glycolytic and gluconeogenic pathways. Additionally, GeneMANIA was used to evaluate interactions, pathways, and attributes of each glycolytic/gluconeogenic steps. The findings reveal that the enzymes and enzymatic isoforms expressed in cell culture were somewhat different from those in breast tissue. We propose that the tumor microenvironment plays a crucial role in the expression of glycolytic and gluconeogenic enzymes and isoforms in tumour cells. Nonetheless, they not only participate in glycolytic and gluconeogenic enzymatic activities but may also influence other pathways, such as the Pentose-Phosphate-Pathway, TCA cycle, as well as other carbohydrate, lipid, and amino acid metabolism.
Collapse
Affiliation(s)
- Carla Luís
- Biochemistry Unit, Department of Biomedicine, Faculty of Medicine, University of Porto (FMUP), Porto, Portugal; i3S - Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Porto, Portugal.
| | - Rúben Fernandes
- Faculty of Health Sciences, University Fernando Pessoa, Fernando Pessoa Hospital School (FCS/HEFP/UFP), Porto, Portugal
| | - Raquel Soares
- Biochemistry Unit, Department of Biomedicine, Faculty of Medicine, University of Porto (FMUP), Porto, Portugal; i3S - Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Porto, Portugal
| |
Collapse
|
35
|
Kuppusamy P, Haque MM, Traub RJ, Melemedjian OK. Targeting metabolic pathways alleviates bortezomib-induced neuropathic pain without compromising anticancer efficacy in a sex-specific manner. FRONTIERS IN PAIN RESEARCH 2024; 5:1424348. [PMID: 38979441 PMCID: PMC11228363 DOI: 10.3389/fpain.2024.1424348] [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: 04/27/2024] [Accepted: 06/10/2024] [Indexed: 07/10/2024] Open
Abstract
Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of cancer treatment that significantly impacts patients' quality of life. This study investigated the effects of targeting metabolic pathways on bortezomib-induced neuropathic pain and tumor growth using a Lewis lung carcinoma (LLC) mouse model, while exploring potential sex differences. Methods Male and female C57BL/6J mice were implanted with LLC cells and treated with bortezomib alone or in combination with metformin, dichloroacetate (DCA), or oxamate. Tactile allodynia was assessed using von Frey filaments. Tumor volume and weight were measured to evaluate tumor growth. Results Metformin, DCA, and oxamate effectively attenuated bortezomib-induced neuropathic pain without compromising the anticancer efficacy of bortezomib in both male and female mice. The LLC model exhibited a paraneoplastic neuropathy-like phenotype. Significant sex differences were observed, with male mice exhibiting larger tumors compared to females. Oxamate was more effective in alleviating allodynia in males, while metformin and DCA showed greater efficacy in reducing tumor growth in females. Discussion Targeting metabolic pathways can alleviate CIPN without interfering with bortezomib's anticancer effects. The LLC model may serve as a tool for studying paraneoplastic neuropathy. Sex differences in tumor growth and response to metabolic interventions highlight the importance of considering sex as a biological variable in preclinical and clinical studies investigating cancer biology, CIPN, and potential therapeutic interventions.
Collapse
Affiliation(s)
- Panjamurthy Kuppusamy
- Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD, United States
| | - Md Mamunul Haque
- Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD, United States
| | - Richard J. Traub
- Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD, United States
- UM Center to Advance Chronic Pain Research, Baltimore, MD, United States
| | - Ohannes K. Melemedjian
- Department of Neural and Pain Sciences, University of Maryland School of Dentistry, Baltimore, MD, United States
- UM Center to Advance Chronic Pain Research, Baltimore, MD, United States
- UM Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States
| |
Collapse
|
36
|
Kim SH, Li ITS. Altering Cell Junctional Tension in Spheroids through E-Cadherin Engagement Modulation. ACS APPLIED BIO MATERIALS 2024; 7:3766-3776. [PMID: 38729097 DOI: 10.1021/acsabm.4c00142] [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] [Indexed: 05/12/2024]
Abstract
Cadherin-mediated tension at adherens junctions (AJs) is fundamental for cell-cell adhesion and maintaining epithelial integrity. Despite the importance of manipulating AJs to dissect cell-cell interactions, existing three-dimensional (3D) multicellular models have not adequately addressed the precise manipulation of these junctions. To fill this gap, we introduce E-cadherin-modified tension gauge tethers (TGTs) at the junctions within spheroids. The system enables both quantification and modulation of junctional tension with specific DNA triggers. Using rupture-induced fluorescence, we successfully measure mechanical forces in 3D spheroids. Furthermore, mechanically strong TGTs can maintain normal E-cadherin-mediated adhesion. Employing toehold-mediated strand displacement allowed us to disrupt E-cadherin-specific cell-cell adhesion, consequently altering intracellular tension within the spheroids. Our methodology offers a robust and precise way to manipulate cell-cell adhesion and intracellular mechanics in spheroid models.
Collapse
Affiliation(s)
- Seong Ho Kim
- Department of Chemistry, The University of British Columbia, Kelowna, British Columbia V1 V 1 V7, Canada
| | - Isaac T S Li
- Department of Chemistry, The University of British Columbia, Kelowna, British Columbia V1 V 1 V7, Canada
| |
Collapse
|
37
|
Xinyi X, Gong Y. The role of ATP-binding cassette subfamily G member 1 in tumor progression. Cancer Med 2024; 13:e7285. [PMID: 38896016 PMCID: PMC11187935 DOI: 10.1002/cam4.7285] [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: 11/24/2023] [Revised: 04/13/2024] [Accepted: 04/30/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND ATP-binding cassette subfamily G member 1 is mostly known as a transporter for intracellular cholesterol efflux, and a number of studies indicate that ABCG1 also functions actively in tumor initiation and progression. This review aimed to provide an overall review of how ABCG1 acts in tumor progression. METHOD A comprehensive searching about ABCG1 and tumor was conducted up to November 2023 using proper keywords through databases including PubMed and Web of Science. RESULT Overall, ABCG1 plays a crucial role in the development of multiple tumorigenesis. ABCG1 enhances tumor-promoting ability through conferring stem-like properties to cancer cells and mediates chemoresistance in multiple cancers. Additionally, ABCG1 may act as a kinase to phosphorylate downstream molecules and induces tumor growth. In tumor microenvironment, ABCG1 plays a substantial role in immunity response through macrophages to create a tumor-favoring circumstance. CONCLUSION High expression of ABCG1 is usually associated with poor prognosis, which means ABCG1 may be a potential biomarker for early diagnosis and prognosis of various cancers. ABCG1-targeted therapy may provide a novel treatment for cancer patients.
Collapse
Affiliation(s)
- Xu Xinyi
- Central Laboratory, The Fifth People's Hospital of ShanghaiFudan UniversityShanghaiChina
| | - Yang Gong
- Central Laboratory, The Fifth People's Hospital of ShanghaiFudan UniversityShanghaiChina
- Cancer InstituteFudan University Shanghai Cancer CenterShanghaiChina
- Department of OncologyFudan University Shanghai Medical SchoolShanghaiChina
| |
Collapse
|
38
|
Han J, Dong H, Zhu T, Wei Q, Wang Y, Wang Y, Lv Y, Mu H, Huang S, Zeng K, Xu J, Ding J. Biochemical hallmarks-targeting antineoplastic nanotherapeutics. Bioact Mater 2024; 36:427-454. [PMID: 39044728 PMCID: PMC11263727 DOI: 10.1016/j.bioactmat.2024.05.042] [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: 02/20/2024] [Revised: 05/18/2024] [Accepted: 05/27/2024] [Indexed: 07/25/2024] Open
Abstract
Tumor microenvironments (TMEs) have received increasing attention in recent years as they play pivotal roles in tumorigenesis, progression, metastases, and resistance to the traditional modalities of cancer therapy like chemotherapy. With the rapid development of nanotechnology, effective antineoplastic nanotherapeutics targeting the aberrant hallmarks of TMEs have been proposed. The appropriate design and fabrication endow nanomedicines with the abilities for active targeting, TMEs-responsiveness, and optimization of physicochemical properties of tumors, thereby overcoming transport barriers and significantly improving antineoplastic therapeutic benefits. This review begins with the origins and characteristics of TMEs and discusses the latest strategies for modulating the TMEs by focusing on the regulation of biochemical microenvironments, such as tumor acidosis, hypoxia, and dysregulated metabolism. Finally, this review summarizes the challenges in the development of smart anti-cancer nanotherapeutics for TME modulation and examines the promising strategies for combination therapies with traditional treatments for further clinical translation.
Collapse
Affiliation(s)
- Jing Han
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - He Dong
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Tianyi Zhu
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Qi Wei
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, PR China
| | - Yongheng Wang
- Department of Biomedical Engineering, University of California Davis, One Shields Avenue, Davis, CA, 95616, USA
| | - Yun Wang
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Yu Lv
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Haoran Mu
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Shandeng Huang
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Ke Zeng
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Jing Xu
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, PR China
| |
Collapse
|
39
|
Li S, Liu Z, Chen Q, Chen Y, Ji S. A novel fatty acid metabolism-related signature identifies MUC4 as a novel therapy target for esophageal squamous cell carcinoma. Sci Rep 2024; 14:12476. [PMID: 38816411 PMCID: PMC11139939 DOI: 10.1038/s41598-024-62917-z] [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: 03/04/2024] [Accepted: 05/22/2024] [Indexed: 06/01/2024] Open
Abstract
Fatty acid metabolism has been identified as an emerging hallmark of cancer, which was closely associated with cancer prognosis. Whether fatty acid metabolism-related genes (FMGs) signature play a more crucial role in biological behavior of esophageal squamous cell carcinoma (ESCC) prognosis remains unknown. Thus, we aimed to identify a reliable FMGs signature for assisting treatment decisions and prognosis evaluation of ESCC. In the present study, we conducted consensus clustering analysis on 259 publicly available ESCC samples. The clinical information was downloaded from The Cancer Genome Atlas (TCGA, 80 ESCC samples) and Gene Expression Omnibus (GEO) database (GSE53625, 179 ESCC samples). A consensus clustering arithmetic was used to determine the FMGs molecular subtypes, and survival outcomes and immune features were evaluated among the different subtypes. Kaplan-Meier analysis and the receiver operating characteristic (ROC) was applied to evaluate the reliability of the risk model in training cohort, validation cohort and all cohorts. A nomogram to predict patients' 1-year, 3-year and 5-year survival rate was also studied. Finally, CCK-8 assay, wound healing assay, and transwell assay were implemented to evaluate the inherent mechanisms of FMGs for tumorigenesis in ESCC. Two subtypes were identified by consensus clustering, of which cluster 2 is preferentially associated with poor prognosis, lower immune cell infiltration. A fatty acid (FA) metabolism-related risk model containing eight genes (FZD10, TACSTD2, MUC4, PDLIM1, PRSS12, BAALC, DNAJA2 and ALOX12B) was established. High-risk group patients displayed worse survival, higher stromal, immune and ESTIMATE scores than in the low-risk group. Moreover, a nomogram revealed good predictive ability of clinical outcomes in ESCC patients. The results of qRT-PCR analysis revealed that the MUC4 and BAALC had high expression level, and FZD10, PDLIM1, TACSTD2, ALOX12B had low expression level in ESCC cells. In vitro, silencing MUC4 remarkably inhibited ESCC cell proliferation, invasion and migration. Our study fills the gap of FMGs signature in predicting the prognosis of ESCC patients. These findings revealed that cluster subtypes and risk model of FMGs had effects on survival prediction, and were expected to be the potential promising targets for ESCC.
Collapse
Affiliation(s)
- Shanshan Li
- Department of Operating Room, Weifang Traditional Chinese Hospital, Weifang, China
| | - Zhengcao Liu
- Department of Radiotherapy & Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, No.16 Baita Road, Suzhou, 215001, China
| | - Qingqing Chen
- Department of Radiotherapy & Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, No.16 Baita Road, Suzhou, 215001, China
| | - Yuetong Chen
- Department of Radiotherapy & Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, No.16 Baita Road, Suzhou, 215001, China
| | - Shengjun Ji
- Department of Radiotherapy & Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, No.16 Baita Road, Suzhou, 215001, China.
| |
Collapse
|
40
|
Han S, Chen Y, Huang Y, Jin L, Ma Y. Arecoline promotes Akt-c-Myc-driven aerobic glycolysis in esophageal epithelial cells. ENVIRONMENTAL TOXICOLOGY 2024; 39:2794-2802. [PMID: 38282581 DOI: 10.1002/tox.24159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 01/02/2024] [Accepted: 01/18/2024] [Indexed: 01/30/2024]
Abstract
Aerobic glycolysis is a typical metabolic rearrangement for tumorigenesis. Arecoline is of explicit carcinogenicity, numerous works demonstrate its mutagenicity, genotoxicity, and cytotoxicity. However, the effects of arecoline on aerobic glycolysis of esophageal epithelial cells remain unclear. In the present study, 5 μM arecoline efficiently increased HK2 expression to induce aerobic glycolysis in Het-1A-Are and NE2-Are cells. The mechanistic analysis showed that arecoline activated the Akt-c-Myc signaling pathway and reduced the GSK3β-mediated phosphorylation of c-Myc on Thr58 to prevent its ubiquitination and destruction, subsequently promoting HK2 transcription and expression. Taken together, these results suggest that arecoline can induce aerobic glycolysis of esophageal epithelial cells and further confirm that arecoline is a carcinogen harmful to human health.
Collapse
Affiliation(s)
- Shuangze Han
- Department of Cardiothoracic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingji Chen
- Department of Cardiothoracic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yu Huang
- Department of Cardiothoracic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Longyu Jin
- Department of Cardiothoracic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yuchao Ma
- Department of Cardiothoracic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| |
Collapse
|
41
|
Li L, Soyhan I, Warszawik E, van Rijn P. Layered Double Hydroxides: Recent Progress and Promising Perspectives Toward Biomedical Applications. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306035. [PMID: 38501901 PMCID: PMC11132086 DOI: 10.1002/advs.202306035] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Indexed: 03/20/2024]
Abstract
Layered double hydroxides (LDHs) have been widely studied for biomedical applications due to their excellent properties, such as good biocompatibility, degradability, interlayer ion exchangeability, high loading capacity, pH-responsive release, and large specific surface area. Furthermore, the flexibility in the structural composition and ease of surface modification of LDHs makes it possible to develop specifically functionalized LDHs to meet the needs of different applications. In this review, the recent advances of LDHs for biomedical applications, which include LDH-based drug delivery systems, LDHs for cancer diagnosis and therapy, tissue engineering, coatings, functional membranes, and biosensors, are comprehensively discussed. From these various biomedical research fields, it can be seen that there is great potential and possibility for the use of LDHs in biomedical applications. However, at the same time, it must be recognized that the actual clinical translation of LDHs is still very limited. Therefore, the current limitations of related research on LDHs are discussed by combining limited examples of actual clinical translation with requirements for clinical translation of biomaterials. Finally, an outlook on future research related to LDHs is provided.
Collapse
Affiliation(s)
- Lei Li
- Department of Biomedical EngineeringUniversity of GroningenUniversity Medical Center GroningenA. Deusinglaan 1Groningen, AV9713The Netherlands
- W. J. Kolff Institute for Biomedical Engineering and Materials ScienceUniversity of GroningenUniversity Medical Center GroningenA. Deusinglaan 1Groningen, AV9713The Netherlands
| | - Irem Soyhan
- Department of Biomedical EngineeringUniversity of GroningenUniversity Medical Center GroningenA. Deusinglaan 1Groningen, AV9713The Netherlands
- W. J. Kolff Institute for Biomedical Engineering and Materials ScienceUniversity of GroningenUniversity Medical Center GroningenA. Deusinglaan 1Groningen, AV9713The Netherlands
| | - Eliza Warszawik
- Department of Biomedical EngineeringUniversity of GroningenUniversity Medical Center GroningenA. Deusinglaan 1Groningen, AV9713The Netherlands
- W. J. Kolff Institute for Biomedical Engineering and Materials ScienceUniversity of GroningenUniversity Medical Center GroningenA. Deusinglaan 1Groningen, AV9713The Netherlands
| | - Patrick van Rijn
- Department of Biomedical EngineeringUniversity of GroningenUniversity Medical Center GroningenA. Deusinglaan 1Groningen, AV9713The Netherlands
- W. J. Kolff Institute for Biomedical Engineering and Materials ScienceUniversity of GroningenUniversity Medical Center GroningenA. Deusinglaan 1Groningen, AV9713The Netherlands
| |
Collapse
|
42
|
Alves S, Santos-Pereira C, Oliveira CSF, Preto A, Chaves SR, Côrte-Real M. Enhancement of Acetate-Induced Apoptosis of Colorectal Cancer Cells by Cathepsin D Inhibition Depends on Oligomycin A-Sensitive Respiration. Biomolecules 2024; 14:473. [PMID: 38672489 PMCID: PMC11048611 DOI: 10.3390/biom14040473] [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: 03/18/2024] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of death worldwide. Conventional therapies are available with varying effectiveness. Acetate, a short-chain fatty acid produced by human intestinal bacteria, triggers mitochondria-mediated apoptosis preferentially in CRC but not in normal colonocytes, which has spurred an interest in its use for CRC prevention/therapy. We previously uncovered that acetate-induced mitochondrial-mediated apoptosis in CRC cells is significantly enhanced by the inhibition of the lysosomal protease cathepsin D (CatD), which indicates both mitochondria and the lysosome are involved in the regulation of acetate-induced apoptosis. Herein, we sought to determine whether mitochondrial function affects CatD apoptotic function. We found that enhancement of acetate-induced apoptosis by CatD inhibition depends on oligomycin A-sensitive respiration. Mechanistically, the potentiating effect is associated with an increase in cellular and mitochondrial superoxide anion accumulation and mitochondrial mass. Our results provide novel clues into the regulation of CatD function and the effect of tumor heterogeneity in the outcome of combined treatment using acetate and CatD inhibitors.
Collapse
Affiliation(s)
| | | | | | | | - Susana R. Chaves
- CBMA—Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, 4710-057 Braga, Portugal; (S.A.); (C.S.-P.); (C.S.F.O.); (A.P.)
| | - Manuela Côrte-Real
- CBMA—Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, 4710-057 Braga, Portugal; (S.A.); (C.S.-P.); (C.S.F.O.); (A.P.)
| |
Collapse
|
43
|
Alhozeel B, Pandey SK, Shteinfer-Kuzmine A, Santhanam M, Shoshan-Barmatz V. Silencing the Mitochondrial Gatekeeper VDAC1 as a Potential Treatment for Bladder Cancer. Cells 2024; 13:627. [PMID: 38607066 PMCID: PMC11012128 DOI: 10.3390/cells13070627] [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: 02/18/2024] [Revised: 03/11/2024] [Accepted: 03/14/2024] [Indexed: 04/13/2024] Open
Abstract
The strategy for treating bladder cancer (BC) depends on whether there is muscle invasion or not, with the latter mostly treated with intravesical therapy, such as with bacillus Calmette-Guérin (BCG). However, BCG treatment is unsuccessful in 70% of patients, who are then subjected to radical cystectomy. Although immune-checkpoint inhibitors have been approved as a second-line therapy for a subset of BC patients, these have failed to meet primary endpoints in clinical trials. Thus, it is crucial to find a new treatment. The mitochondrial gatekeeper protein, the voltage-dependent anion channel 1 (VDAC1), mediates metabolic crosstalk between the mitochondria and cytosol and is involved in apoptosis. It is overexpressed in many cancer types, as shown here for BC, pointing to its significance in high-energy-demanding cancer cells. The BC cell lines UM-UC3 and HTB-5 express high VDAC1 levels compared to other cancer cell lines. VDAC1 silencing in these cells using siRNA that recognizes both human and mouse VDAC1 (si-m/hVDAC1-B) reduces cell viability, mitochondria membrane potential, and cellular ATP levels. Here, we used two BC mouse models: subcutaneous UM-UC3 cells and chemically induced BC using the carcinogen N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Subcutaneous UM-UC3-derived tumors treated with si-m/hVDAC1 showed inhibited tumor growth and reprogrammed metabolism, as reflected in the reduced expression of metabolism-related proteins, including Glut1, hexokinase, citrate synthase, complex-IV, and ATP synthase, suggesting reduced metabolic activity. Furthermore, si-m/hVDAC1-B reduced the expression levels of cancer-stem-cell-related proteins (cytokeratin-14, ALDH1a), modifying the tumor microenvironment, including decreased angiogenesis, extracellular matrix, tumor-associated macrophages, and inhibited epithelial-mesenchymal transition. The BBN-induced BC mouse model showed a clear carcinoma, with damaged bladder morphology and muscle-invasive tumors. Treatment with si-m/hVDAC1-B encapsulated in PLGA-PEI nanoparticles that were administered intravesically directly to the bladder showed a decreased tumor area and less bladder morphology destruction and muscle invasion. Overall, the obtained results point to the potential of si-m/hVDAC1-B as a possible therapeutic tool for treating bladder cancer.
Collapse
Affiliation(s)
- Belal Alhozeel
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (B.A.); (S.K.P.); (M.S.)
| | - Swaroop Kumar Pandey
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (B.A.); (S.K.P.); (M.S.)
| | - Anna Shteinfer-Kuzmine
- National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
| | - Manikandan Santhanam
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (B.A.); (S.K.P.); (M.S.)
- National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
| | - Varda Shoshan-Barmatz
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (B.A.); (S.K.P.); (M.S.)
- National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
| |
Collapse
|
44
|
Rawat SG, Tiwari RK, Kumar A. Blockade of phosphodiesterase 5 by sildenafil reduces tumor growth and potentiates tumor-killing ability of cisplatin in vivo against T cell lymphoma: Implication of modulated apoptosis, reactive oxygen species homeostasis, glucose metabolism, and pH regulation. ENVIRONMENTAL TOXICOLOGY 2024; 39:1909-1922. [PMID: 38059649 DOI: 10.1002/tox.24074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/25/2023] [Accepted: 11/12/2023] [Indexed: 12/08/2023]
Abstract
In the past years, PDE5 has emerged as a promising therapeutic target for many cancers due to its highly upregulated expression. Interestingly, a recent in vitro study by our group has shown the antitumor and chemopotentiating action of sildenafil against T cell lymphoma. Our study showed that lower doses of sildenafil (50 μM) and cisplatin (0.5 μg/mL) exhibited 4% and 23% cytotoxicity against HuT78 cells, respectively, which was dramatically increased up to 50% when treated with both. Hence, the present study was designed to evaluate the antitumor and chemo-potentiating action of sildenafil in a murine model of T cell lymphoma (popularly called as Dalton's lymphoma [DL]). In the present study, DL-bearing mice were administered with vehicle (PBS), sildenafil (5 mg/kg bw), cisplatin (5 mg/kg bw), and sildenafil and cisplatin followed by evaluation of their impact on tumor growth by analyzing various parameters. The apoptosis was assessed by Wright-Giemsa, annexin-V, and DAPI staining. Reactive oxygen species (ROS) level was examined through DCFDA staining. The expression of genes and proteins were estimated by RT-PCR and Western blotting, respectively. The experimental findings of the study demonstrate for the first time that sildenafil inhibits tumor growth and potentiates tumor inhibitory ability of cisplatin by altering apoptosis, glycolysis, ROS homeostasis, and pH regulation in T cell lymphoma-carrying host. In addition, our investigation also showed amelioration of tumor-induced liver and kidney damage by sildenafil. Overall, the experimental data of our study strongly advocate the use and repurposing of SDF in designing promising chemotherapeutic regimens against malignancies of T cells.
Collapse
Affiliation(s)
- Shiv Govind Rawat
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Rajan Kumar Tiwari
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Ajay Kumar
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| |
Collapse
|
45
|
Wu Y, Han W, Tang X, Liu J, Guo Z, Li Z, Cai C, Que L. B7-H3 suppresses CD8 + T cell immunologic function through reprogramming glycolytic metabolism. J Cancer 2024; 15:2505-2517. [PMID: 38577598 PMCID: PMC10988323 DOI: 10.7150/jca.90819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 03/02/2024] [Indexed: 04/06/2024] Open
Abstract
Malignant neoplasms pose a formidable threat to human well-being. Prior studies have documented the extensive expression of B7 homolog 3 (B7-H3 or CD276) across various tumors, affecting glucose metabolism. Yet, the link between metabolic modulation and immune responses remains largely unexplored. Our study reveals a significant association between B7-H3 expression and advanced tumor stages, lymph node metastasis, and tumor location in oral squamous cell carcinoma (OSCC). We further elucidate B7-H3's role in mediating glucose competition between cancer cells and CD8+ T cells. Through co-culturing tumor cells with flow cytometry-sorted CD8+ T cells, we measured glucose uptake and lactate secretion in both cell types. Additionally, we assessed interferon-gamma (IFN-γ) release and the immune and exhaustion status of CD8+ T cells. Our findings indicate that B7-H3 enhances glycolysis in OSCC and malignant melanoma, while simultaneously inhibiting CD8+ T cell glycolysis. Silencing B7-H3 led to increased IFN-γ secretion in co-cultures, highlighting its significant role in modulating CD8+ T cell functions within the tumor microenvironment and its impact on tumorigenicity. We also demonstrate that glycolysis inhibition can be mitigated by exogenous glucose supplementation. Mechanistically, our study suggests B7-H3's influence on metabolism might be mediated through the phosphoinositide3-kinase (PI3K)/ protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway. This research unveils how B7-H3 affects immune functions via metabolic reprogramming.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Lin Que
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China
| |
Collapse
|
46
|
Liao M, Yao D, Wu L, Luo C, Wang Z, Zhang J, Liu B. Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer. Acta Pharm Sin B 2024; 14:953-1008. [PMID: 38487001 PMCID: PMC10935242 DOI: 10.1016/j.apsb.2023.12.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 11/09/2023] [Accepted: 11/14/2023] [Indexed: 03/17/2024] Open
Abstract
Cancer reprogramming is an important facilitator of cancer development and survival, with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation, even under sufficient oxygen supply condition. This metabolic alteration, known as the Warburg effect, serves as a significant indicator of malignant tumor transformation. The Warburg effect primarily impacts cancer occurrence by influencing the aerobic glycolysis pathway in cancer cells. Key enzymes involved in this process include glucose transporters (GLUTs), HKs, PFKs, LDHs, and PKM2. Moreover, the expression of transcriptional regulatory factors and proteins, such as FOXM1, p53, NF-κB, HIF1α, and c-Myc, can also influence cancer progression. Furthermore, lncRNAs, miRNAs, and circular RNAs play a vital role in directly regulating the Warburg effect. Additionally, gene mutations, tumor microenvironment remodeling, and immune system interactions are closely associated with the Warburg effect. Notably, the development of drugs targeting the Warburg effect has exhibited promising potential in tumor treatment. This comprehensive review presents novel directions and approaches for the early diagnosis and treatment of cancer patients by conducting in-depth research and summarizing the bright prospects of targeting the Warburg effect in cancer.
Collapse
Affiliation(s)
- Minru Liao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dahong Yao
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen 518118, China
| | - Lifeng Wu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chaodan Luo
- Department of Psychology, University of Southern California, Los Angeles, CA 90089, USA
| | - Zhiwen Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen 518118, China
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Jin Zhang
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Bo Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| |
Collapse
|
47
|
Dhanyamraju PK. Drug resistance mechanisms in cancers: Execution of pro-survival strategies. J Biomed Res 2024; 38:95-121. [PMID: 38413011 PMCID: PMC11001593 DOI: 10.7555/jbr.37.20230248] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/21/2023] [Accepted: 12/07/2023] [Indexed: 02/29/2024] Open
Abstract
One of the quintessential challenges in cancer treatment is drug resistance. Several mechanisms of drug resistance have been described to date, and new modes of drug resistance continue to be discovered. The phenomenon of cancer drug resistance is now widespread, with approximately 90% of cancer-related deaths associated with drug resistance. Despite significant advances in the drug discovery process, the emergence of innate and acquired mechanisms of drug resistance has impeded the progress in cancer therapy. Therefore, understanding the mechanisms of drug resistance and the various pathways involved is integral to treatment modalities. In the present review, I discuss the different mechanisms of drug resistance in cancer cells, including DNA damage repair, epithelial to mesenchymal transition, inhibition of cell death, alteration of drug targets, inactivation of drugs, deregulation of cellular energetics, immune evasion, tumor-promoting inflammation, genome instability, and other contributing epigenetic factors. Furthermore, I highlight available treatment options and conclude with future directions.
Collapse
Affiliation(s)
- Pavan Kumar Dhanyamraju
- Fels Cancer Institute of Personalized Medicine, Lewis-Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| |
Collapse
|
48
|
Kim YH, Yoon SJ, Kim M, Kim HH, Song YS, Jung JW, Han D, Cho SW, Kwon SW, Park YJ. Integrative Multi-omics Analysis Reveals Different Metabolic Phenotypes Based on Molecular Characteristics in Thyroid Cancer. Clin Cancer Res 2024; 30:883-894. [PMID: 38088902 DOI: 10.1158/1078-0432.ccr-23-2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/06/2023] [Accepted: 12/11/2023] [Indexed: 02/17/2024]
Abstract
PURPOSE Thyroid cancer metabolic characteristics vary depending on the molecular subtype determined by mutational status. We aimed to investigate the molecular subtype-specific metabolic characteristics of thyroid cancers. EXPERIMENTAL DESIGN An integrative multi-omics analysis was conducted, incorporating transcriptomics, metabolomics, and proteomics data obtained from human tissues representing distinct molecular characteristics of thyroid cancers: BRAF-like (papillary thyroid cancer with BRAFV600E mutation; PTC-B), RAS-like (follicular thyroid cancer with RAS mutation; FTC-R), and ATC-like (anaplastic thyroid cancer with BRAFV600E or RAS mutation; ATC-B or ATC-R). To validate our findings, we employed tissue microarray of human thyroid cancer tissues and performed in vitro analyses of cancer cell phenotypes and metabolomic assays after inducing genetic knockdown. RESULTS Metabolic properties differed between differentiated thyroid cancers of PTC-B and FTC-R, but were similar in dedifferentiated thyroid cancers of ATC-B/R, regardless of their mutational status. Tricarboxylic acid (TCA) intermediates and branched-chain amino acids (BCAA) were enriched with the activation of TCA cycle only in FTC-R, whereas one-carbon metabolism and pyrimidine metabolism increased in both PTC-B and FTC-R and to a great extent in ATC-B/R. However, the protein expression levels of the BCAA transporter (SLC7A5) and a key enzyme in one-carbon metabolism (SHMT2) increased in all thyroid cancers and were particularly high in ATC-B/R. Knockdown of SLC7A5 or SHMT2 inhibited the migration and proliferation of thyroid cancer cell lines differently, depending on the mutational status. CONCLUSIONS These findings define the metabolic properties of each molecular subtype of thyroid cancers and identify metabolic vulnerabilities, providing a rationale for therapies targeting its altered metabolic pathways in advanced thyroid cancer.
Collapse
Affiliation(s)
- Yoo Hyung Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, the Republic of South Korea
| | - Sang Jun Yoon
- Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, the Republic of South Korea
| | - Mina Kim
- Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, the Republic of South Korea
| | - Hwan Hee Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, the Republic of South Korea
| | - Young Shin Song
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, the Republic of South Korea
| | - Jin Woo Jung
- Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul, the Republic of South Korea
| | - Dohyun Han
- Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul, the Republic of South Korea
- Transdisciplinary Department of Medicine & Advanced Technology, Seoul National University Hospital, Seoul, the Republic of South Korea
| | - Sun Wook Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, the Republic of South Korea
| | - Sung Won Kwon
- Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, the Republic of South Korea
| | - Young Joo Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul, the Republic of South Korea
- Department of Internal Medicine and Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, the Republic of South Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, the Republic of South Korea
| |
Collapse
|
49
|
Mostafavi S, Eskandari N. Mitochondrion: Main organelle in orchestrating cancer escape from chemotherapy. Cancer Rep (Hoboken) 2024; 7:e1942. [PMID: 38151790 PMCID: PMC10849933 DOI: 10.1002/cnr2.1942] [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: 08/03/2023] [Revised: 10/23/2023] [Accepted: 11/12/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND Chemoresistance is a challenging barrier to cancer therapy, and in this context, the role of mitochondria is significant. We put emphasis on key biological characteristics of mitochondria, contributing to tumor escape from various therapies, to find the "Achilles' Heel" of cancer cells for future drug design. RECENT FINDINGS The mitochondrion is a dynamic organelle, and its existence is important for tumor growth. Its metabolites also cooperate with cell signaling in tumor proliferation and drug resistance. CONCLUSION Biological characteristics of this organelle, such as redox balance, DNA depletion, and metabolic reprogramming, provide flexibility to cancer cells to cope with therapy-induced stress.
Collapse
Affiliation(s)
- Samaneh Mostafavi
- Department of Immunology, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran
| | - Nahid Eskandari
- Department of Immunology, Faculty of MedicineIsfahan University of Medical ScienceIsfahanIran
| |
Collapse
|
50
|
Chiou YY, Lee CY, Yang HW, Cheng WC, Ji KD. Circadian modulation of glucose utilization via CRY1-mediated repression of Pdk1 expression. J Biol Chem 2024; 300:105637. [PMID: 38199564 PMCID: PMC10869264 DOI: 10.1016/j.jbc.2024.105637] [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: 11/15/2023] [Revised: 12/21/2023] [Accepted: 12/30/2023] [Indexed: 01/12/2024] Open
Abstract
Life adapts to daily environmental changes through circadian rhythms, exhibiting spontaneous oscillations of biological processes. These daily functional oscillations must match the metabolic requirements responding to the time of the day. We focus on the molecular mechanism of how the circadian clock regulates glucose, the primary resource for energy production and other biosynthetic pathways. The complex regulation of the circadian rhythm includes many proteins that control this process at the transcriptional and translational levels and by protein-protein interactions. We have investigated the action of one of these proteins, cryptochrome (CRY), whose elevated mRNA and protein levels repress the function of an activator in the transcription-translation feedback loop, and this activator causes elevated Cry1 mRNA. We used a genome-edited cell line model to investigate downstream genes affected explicitly by the repressor CRY. We found that CRY can repress glycolytic genes, particularly that of the gatekeeper, pyruvate dehydrogenase kinase 1 (Pdk1), decreasing lactate accumulation and glucose utilization. CRY1-mediated decrease of Pdk1 expression can also be observed in a breast cancer cell line MDA-MB-231, whose glycolysis is associated with Pdk1 expression. We also found that exogenous expression of CRY1 in the MDA-MB-231 decreases glucose usage and growth rate. Furthermore, reduced CRY1 levels and the increased phosphorylation of PDK1 substrate were observed when cells were grown in suspension compared to cells grown in adhesion. Our data supports a model that the transcription-translation feedback loop can regulate the glucose metabolic pathway through Pdk1 gene expression according to the time of the day.
Collapse
Affiliation(s)
- Yi-Ying Chiou
- Graduate Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
| | - Cing-Yun Lee
- Graduate Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Hao-Wei Yang
- Graduate Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Wei-Cheng Cheng
- Graduate Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Kun-Da Ji
- Graduate Institute of Biochemistry, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan
| |
Collapse
|