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Zhang Y, Zhang Y, Xiao Y, Xu S, Li J, Li J, Chang L, Ding J, Wu D, Wang L, Xu G, Wang K. Investigating the role of MicroRNA-519d-3p in enhancing chemosensitivity of colorectal cancer cells to 5-Fluorouracil through PFKFB3 targeting. Clinics (Sao Paulo) 2025; 80:100606. [PMID: 40014905 PMCID: PMC11910362 DOI: 10.1016/j.clinsp.2025.100606] [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: 04/06/2024] [Revised: 01/23/2025] [Accepted: 02/15/2025] [Indexed: 03/01/2025] Open
Abstract
OBJECTIVE In the fight against Colorectal Cancer (CRC), chemotherapy resistance is a major obstacle. Therefore, it is imperative to identify effective biomarker therapeutics. Despite microRNAs (miRs) playing a crucial role in drug resistance, the mechanisms comprising miR-519d-3p's role in CRC drug resistance have not been fully understood. Therefore, the present study aimed to investigate the biological function of miR-519d-3p in the chemosensitivity of CRC cells to 5-Fluorouracil (5-FU). METHODS CRC cells were treated with 5-FU and transfected. Cellular proliferation, invasion, and apoptosis were evaluated. The relationship between miR-519d-3p and 6-Phosphofructokinase-2/Frucose-2, 6-Biphosphatase-3 (PFKFB3) was analyzed, and their interaction in CRC was further investigated. In vivo tumor experiments were conducted to investigate the function of miR-519d-3p and 5-FU in CRC. RESULTS As determined, CRC cells overexpressing miR-519d-3p were more sensitive to 5-FU in vitro, as miR-519d-3p inhibits proliferation and invasion and stimulates apoptosis. miR-519d-3p directly targeted PFKFB3. In CRC cells, PFKFB3 overexpression rescued miR-519d-3p-induced 5-FU toxicity. In vivo results showed that mice co-treated with miR-519d-3p mimics and 5-FU showed higher antitumor activity. CONCLUSION Overall, it may be possible to improve 5-FU chemosensitivity of CRC cells by targeting miR-519d-3p and PFKFB3.
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Affiliation(s)
- Yangyang Zhang
- Department of General Practice, The First Affiliated Hospital with Nanjing Medical University, Nanjing City, Jiangsu Province, PR China; Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing City, Jiangsu Province, PR China
| | - Yiqing Zhang
- Professor, Department of Rehabilitation Medicine Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing City, Jiangsu Province, PR China
| | - Yanan Xiao
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing City, Jiangsu Province, PR China
| | - Shufen Xu
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing City, Jiangsu Province, PR China
| | - Jie Li
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing City, Jiangsu Province, PR China
| | - Juan Li
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing City, Jiangsu Province, PR China
| | - Lisha Chang
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing City, Jiangsu Province, PR China
| | - Jie Ding
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing City, Jiangsu Province, PR China
| | - Di Wu
- Department of Rehabilitation Medicine Center, Yixing People's Hospital, Yixing City, Jiangsu Province, PR China
| | - Li Wang
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing City, Jiangsu Province, PR China
| | - Guangxu Xu
- Professor, Department of Rehabilitation Medicine Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing City, Jiangsu Province, PR China
| | - Keming Wang
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing City, Jiangsu Province, PR China.
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Wu H, Fu M, Wu M, Cao Z, Zhang Q, Liu Z. Emerging mechanisms and promising approaches in pancreatic cancer metabolism. Cell Death Dis 2024; 15:553. [PMID: 39090116 PMCID: PMC11294586 DOI: 10.1038/s41419-024-06930-0] [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: 04/18/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 08/04/2024]
Abstract
Pancreatic cancer is an aggressive cancer with a poor prognosis. Metabolic abnormalities are one of the hallmarks of pancreatic cancer, and pancreatic cancer cells can adapt to biosynthesis, energy intake, and redox needs through metabolic reprogramming to tolerate nutrient deficiency and hypoxic microenvironments. Pancreatic cancer cells can use glucose, amino acids, and lipids as energy to maintain malignant growth. Moreover, they also metabolically interact with cells in the tumour microenvironment to change cell fate, promote tumour progression, and even affect immune responses. Importantly, metabolic changes at the body level deserve more attention. Basic research and clinical trials based on targeted metabolic therapy or in combination with other treatments are in full swing. A more comprehensive and in-depth understanding of the metabolic regulation of pancreatic cancer cells will not only enrich the understanding of the mechanisms of disease progression but also provide inspiration for new diagnostic and therapeutic approaches.
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Affiliation(s)
- Hao Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Mengdi Fu
- Department of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Mengwei Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Zhen Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Qiyao Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Ziwen Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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Jiang Z, Gu Z, Lu X, Wen W. The role of dysregulated metabolism and associated genes in gastric cancer initiation and development. Transl Cancer Res 2024; 13:3854-3868. [PMID: 39145068 PMCID: PMC11319955 DOI: 10.21037/tcr-23-2244] [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: 12/06/2023] [Accepted: 06/04/2024] [Indexed: 08/16/2024]
Abstract
The review delves into the intricate interplay between metabolic dysregulation and the onset and progression of gastric cancer (GC), shedding light on a pivotal aspect of this prevalent malignancy. GC stands as one of the leading causes of cancer-related mortality worldwide, its trajectory influenced by a multitude of factors, among which metabolic dysregulation and aberrant gene expression play significant roles. The article navigates through the fundamental roles of metabolic dysregulation in the genesis of GC, unveiling phenomena such as aberrant glycolysis, epitomized by the Warburg effect, alongside anomalies in lipid and amino acid metabolism. It delineates how these disruptions fuel the cancerous process, facilitating uncontrolled cell proliferation and survival. Furthermore, the intricate nexus between metabolism and the vitality of GC cells is elucidated, underscoring the profound influence of metabolic reprogramming on tumor energy dynamics and the accrual of metabolic by-products, which further perpetuate malignant growth. A pivotal segment of the review entails an exploration of key metabolic-related genes implicated in GC pathogenesis. MYC and TP53 are spotlighted among others, delineating their pivotal roles in driving tumorigenesis through metabolic pathway modulation. These genetic pathways serve as critical nodes in the intricate network orchestrating GC development, providing valuable targets for therapeutic intervention. This review embarks on a forward-looking trajectory, delineating the potential therapeutic avenues stemming from insights into metabolic dysregulation in GC. It underscores the promise of targeted therapies directed towards specific metabolic pathways implicated in tumor progression, alongside the burgeoning potential of combination therapy strategies leveraging both metabolic and conventional anti-cancer modalities. In essence, this comprehensive review serves as a beacon, illuminating the intricate landscape of metabolic dysregulation in GC pathogenesis. Through its nuanced exploration of metabolic aberrations and their genetic underpinnings, it not only enriches our understanding of GC biology but also unveils novel therapeutic vistas poised to revolutionize its clinical management.
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Affiliation(s)
- Zhengyan Jiang
- Digestive Department, Jiangsu Second Chinese Medicine Hospital, Nanjing, China
| | - Zhengrong Gu
- Digestive Department, Jiangsu Second Chinese Medicine Hospital, Nanjing, China
| | - Xianyan Lu
- Digestive Department, Suzhou Wujiang District Hospital of Traditional Chinese Medicine (Suzhou Wujiang District Second People’s Hospital), Suzhou, China
| | - Wei Wen
- Digestive Department, Jiangsu Second Chinese Medicine Hospital, Nanjing, China
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Fontana F, Giannitti G, Marchesi S, Limonta P. The PI3K/Akt Pathway and Glucose Metabolism: A Dangerous Liaison in Cancer. Int J Biol Sci 2024; 20:3113-3125. [PMID: 38904014 PMCID: PMC11186371 DOI: 10.7150/ijbs.89942] [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: 09/07/2023] [Accepted: 04/11/2024] [Indexed: 06/22/2024] Open
Abstract
Aberrant activation of the PI3K/Akt pathway commonly occurs in cancers and correlates with multiple aspects of malignant progression. In particular, recent evidence suggests that the PI3K/Akt signaling plays a fundamental role in promoting the so-called aerobic glycolysis or Warburg effect, by phosphorylating different nutrient transporters and metabolic enzymes, such as GLUT1, HK2, PFKB3/4 and PKM2, and by regulating various molecular networks and proteins, including mTORC1, GSK3, FOXO transcription factors, MYC and HIF-1α. This leads to a profound reprogramming of cancer metabolism, also impacting on pentose phosphate pathway, mitochondrial oxidative phosphorylation, de novo lipid synthesis and redox homeostasis and thereby allowing the fulfillment of both the catabolic and anabolic demands of tumor cells. The present review discusses the interactions between the PI3K/Akt cascade and its metabolic targets, focusing on their possible therapeutic implications.
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Affiliation(s)
- Fabrizio Fontana
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy
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Bagheri M, Aghaabdollahian S, Asghardoust Rezaei M, Gholian Kholerdi AM, Raei M, Keyvanloo Shahrestanaki M. Overexpression of Long Non-coding RNAs MCM3AP-AS1 and LINC00092 Predict Poor Prognosis in Patients with Gastric Adenocarcinoma. Adv Biomed Res 2024; 13:34. [PMID: 39234433 PMCID: PMC11373733 DOI: 10.4103/abr.abr_308_23] [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: 08/22/2023] [Revised: 11/01/2023] [Accepted: 11/04/2023] [Indexed: 09/06/2024] Open
Abstract
Background LINC00092 and MCM3AP-AS1 long non-coding RNAs (LncRNAs) play significant roles in the development and pathogenesis of many cancers. However, their expression levels and prognostic values were not evaluated in human gastric adenocarcinoma (GAC). Therefore, the present study aimed to investigate the clinico-pathological correlations of LINC00092 and MCM3AP-AS1, LncRNAs expression in GAC, and evaluate their prognostic values. Materials and Methods The expression of LINC00092 and MCM3AP-AS1 was detected in 89 GAC tissues by quantitative real-time reverse-transcription PCR (qRT-PCR). Results Our results showed that LINC00092 and MCM3AP-AS1 are overexpressed in GAC patients and positively correlated with GAC invasion and vascular, peritoneal, and lymph node metastasis (P < 0.05). Furthermore, the results indicated that MCM3AP-AS1 (P = 0.0225) and LINC00092 (P < 0.001) have positive correlations with GAC patients' overall survival. Conclusion Altogether, the present results indicated that LINC00092 and MCM3AP-AS1 overexpression is associated with clinico-pathological characteristic of GAC patients. In addition, both of these LncRNAs may have prognostic value for estimation of patients' overall survival.
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Affiliation(s)
- Mahdi Bagheri
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | | | | | | - Mehdi Raei
- Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
- Department of Epidemiology and Biostatistics, School of Health, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Chen W, Ye X, Chen Y, Zhao T, Zhou H. M6A methylation of FKFB3 reduced pyroptosis of gastric cancer by NLRP3. Anticancer Drugs 2024; 35:344-357. [PMID: 38241195 DOI: 10.1097/cad.0000000000001574] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2024]
Abstract
Gastric cancer is a kind of malignant tumor that seriously endangers human life and health. Its incidence rate and mortality rate are among the highest in the global malignant tumors. Therefore, this study explored the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the progression of gastric cancer and its underlying mechanism. Patients with gastric cancer were collected, and human GC cell lines (stomach gastric carcinoma 7901, stomach gastric carcinoma 823 , human gastric carcinoma cell line 803 and adenocarcinoma gastric stomach) were used in this study. We utilized glucose consumption, cell migration, and ELISA assay kits to investigate the function of GC. To understand its mechanism, we employed quantitative PCR (qPCR), western blot, and m6A methylated RNA immunoprecipitation assay. FKFB3 protein expression levels in patients with gastric cancer were increased. The induction of PFKFB3 mRNA expression levels in patients with gastric cancer or gastric cancer cell lines. Gastric cancer patients with high PFKFB3 expression had a lower survival rate. PFKFB3 high expression possessed the probability of pathological stage, lymph node metastasis or distant metastasis in patients with gastric cancer. PFKFB3 upregulation promoted cancer progression and Warburg effect progression of gastric cancer. PFKFB3 upregulation reduced pyroptosis and suppressed nucleotidebinding domain, leucinerich repeat containing protein 3-induced pyroptosis of gastric cancer. M6A-forming enzyme methyltransferase-like 3 increased PFKFB3 stability. Taken together, the M6A-forming enzyme methyltransferase-like 3 increased PFKFB3 stability and reduced pyroptosis in the model of gastric cancer through the Warburg effect. The PFKFB3 gene represents a potential therapeutic strategy for the treatment of gastric cancer.
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Affiliation(s)
- Wanyuan Chen
- Cancer Center, Department of Pathology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College
| | - Xiaolin Ye
- College of Basic Medical Science, Zhejiang Chinese Medical University
| | - Yun Chen
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Tongwei Zhao
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Hongying Zhou
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
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Chen Q, Liu Y, Zhu Y, Zhu Z, Zou J, Pan Y, Lu Y, Chen W. Cryptotanshinone inhibits PFK-mediated aerobic glycolysis by activating AMPK pathway leading to blockade of cutaneous melanoma. Chin Med 2024; 19:45. [PMID: 38454519 PMCID: PMC10921599 DOI: 10.1186/s13020-024-00913-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 02/24/2024] [Indexed: 03/09/2024] Open
Abstract
BACKGROUND Cutaneous melanoma is a kind of skin malignancy with low morbidity but high mortality. Cryptotanshinone (CPT), an important component of salvia miltiorrhiza has potent anti-tumor activity and also indicates therapeutic effect on dermatosis. So we thought that CPT maybe a potential agent for therapy of cutaneous melanoma. METHODS B16F10 and A375 melanoma cells were used for in vitro assay. Tumor graft models were made in C57BL/6N and BALB/c nude mice for in vivo assay. Seahorse XF Glycolysis Stress Test Kit was used to detect extracellular acidification rate and oxygen consumption rate. Si-RNAs were used for knocking down adenosine monophosphate-activated protein kinase (AMPK) expression in melanoma cells. RESULTS CPT could inhibit the proliferation of melanoma cells. Meanwhile, CPT changed the glucose metabolism and inhibited phosphofructokinase (PFK)-mediated glycolysis in melanoma cells to a certain extent. Importantly, CPT activated AMPK and inhibited the expression of hypoxia inducible factor 1α (HIF-1α). Both AMPK inhibitor and silencing AMPK could partially reverse CPT's effect on cell proliferation, cell apoptosis and glycolysis. Finally, in vivo experimental data demonstrated that CPT blocked the growth of melanoma, in which was dependent on the glycolysis-mediated cell proliferation. CONCLUSIONS CPT activated AMPK and then inhibited PFK-mediated aerobic glycolysis leading to inhibition of growth of cutaneous melanoma. CPT should be a promising anti-melanoma agent for clinical melanoma therapy.
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Affiliation(s)
- Qiong Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yang Liu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yunxuan Zhu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ziyan Zhu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jueyao Zou
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yanhong Pan
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- Department of Pharmacy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing, China.
- Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing, China.
| | - Wenxing Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing, China.
- Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing, China.
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Liu P, Sun D, Zhang S, Chen S, Wang X, Li H, Wei F. PFKFB3 in neovascular eye disease: unraveling mechanisms and exploring therapeutic strategies. Cell Biosci 2024; 14:21. [PMID: 38341583 DOI: 10.1186/s13578-024-01205-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 02/04/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND Neovascular eye disease is characterized by pathological neovascularization, with clinical manifestations such as intraocular exudation, bleeding, and scar formation, ultimately leading to blindness in millions of individuals worldwide. Pathologic ocular angiogenesis often occurs in common fundus diseases including proliferative diabetic retinopathy (PDR), age-related macular degeneration (AMD), and retinopathy of prematurity (ROP). Anti-vascular endothelial growth factor (VEGF) targets the core pathology of ocular angiogenesis. MAIN BODY In recent years, therapies targeting metabolism to prevent angiogenesis have also rapidly developed, offering assistance to patients with a poor prognosis while receiving anti-VEGF therapy and reducing the side effects associated with long-term VEGF usage. Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key enzyme in targeted metabolism, has been shown to have great potential, with antiangiogenic effects and multiple protective effects in the treatment of neovascular eye disease. In this review, we summarize the mechanisms of common types of neovascular eye diseases; discuss the protective effect and potential mechanism of targeting PFKFB3, including the related inhibitors of PFKFB3; and look forward to the future exploration directions and therapeutic prospects of PFKFB3 in neovascular eye disease. CONCLUSION Neovascular eye disease, the most common and severely debilitating retinal disease, is largely incurable, necessitating the exploration of new treatment methods. PFKFB3 has been shown to possess various potential protective mechanisms in treating neovascular eye disease. With the development of several drugs targeting PFKFB3 and their gradual entry into clinical research, targeting PFKFB3-mediated glycolysis has emerged as a promising therapeutic approach for the future of neovascular eye disease.
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Affiliation(s)
- Peiyu Liu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, National Clinical Research Center for Eye Diseases, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China
| | - Dandan Sun
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, National Clinical Research Center for Eye Diseases, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China
| | - Shuchang Zhang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, National Clinical Research Center for Eye Diseases, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China
| | - Shimei Chen
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, National Clinical Research Center for Eye Diseases, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China
| | - Xiaoqian Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, National Clinical Research Center for Eye Diseases, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China
| | - Huiming Li
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Fang Wei
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, National Clinical Research Center for Eye Diseases, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China.
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Campos M, Albrecht LV. Hitting the Sweet Spot: How Glucose Metabolism Is Orchestrated in Space and Time by Phosphofructokinase-1. Cancers (Basel) 2023; 16:16. [PMID: 38201444 PMCID: PMC10778546 DOI: 10.3390/cancers16010016] [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: 11/07/2023] [Revised: 12/12/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Glycolysis is the central metabolic pathway across all kingdoms of life. Intensive research efforts have been devoted to understanding the tightly orchestrated processes of converting glucose into energy in health and disease. Our review highlights the advances in knowledge of how metabolic and gene networks are integrated through the precise spatiotemporal compartmentalization of rate-limiting enzymes. We provide an overview of technically innovative approaches that have been applied to study phosphofructokinase-1 (PFK1), which represents the fate-determining step of oxidative glucose metabolism. Specifically, we discuss fast-acting chemical biology and optogenetic tools that have delineated new links between metabolite fluxes and transcriptional reprogramming, which operate together to enact tissue-specific processes. Finally, we discuss how recent paradigm-shifting insights into the fundamental basis of glycolytic regulatory control have shed light on the mechanisms of tumorigenesis and could provide insight into new therapeutic vulnerabilities in cancer.
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Affiliation(s)
- Melissa Campos
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, CA 92697, USA;
| | - Lauren V. Albrecht
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California, Irvine, CA 92697, USA;
- Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA
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Zhao L, Ma D, Wang L, Su X, Feng L, Zhu L, Chen Y, Hao Y, Wang X, Feng J. Metabolic changes with the occurrence of atherosclerotic plaques and the effects of statins. Front Immunol 2023; 14:1301051. [PMID: 38143759 PMCID: PMC10739339 DOI: 10.3389/fimmu.2023.1301051] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/23/2023] [Indexed: 12/26/2023] Open
Abstract
Atherosclerosis is a common cardiovascular disease caused by the abnormal expression of multiple factors and genes influenced by both environmental and genetic factors. The primary manifestation of atherosclerosis is plaque formation, which occurs when inflammatory cells consume excess lipids, affecting their retention and modification within the arterial intima. This triggers endothelial cell (EC) activation, immune cell infiltration, vascular smooth muscle cell (VSMC) proliferation and migration, foam cell formation, lipid streaks, and fibrous plaque development. These processes can lead to vascular wall sclerosis, lumen stenosis, and thrombosis. Immune cells, ECs, and VSMCs in atherosclerotic plaques undergo significant metabolic changes and inflammatory responses. The interaction of cytokines and chemokines secreted by these cells leads to the onset, progression, and regression of atherosclerosis. The regulation of cell- or cytokine-based immune responses is a novel therapeutic approach for atherosclerosis. Statins are currently the primary pharmacological agents utilised for managing unstable plaques owing to their ability to enhance endothelial function, regulate VSMC proliferation and apoptosis by reducing cholesterol levels, and mitigate the expression and activity of inflammatory cytokines. In this review, we provide an overview of the metabolic changes associated with atherosclerosis, describe the effects of inflammatory responses on atherosclerotic plaques, and discuss the mechanisms through which statins contribute to plaque stabilisation. Additionally, we examine the role of statins in combination with other drugs in the management of atherosclerosis.
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Affiliation(s)
| | - Di Ma
- Bethune First Hospital, Jilin University, Changchun, China
| | - LiJuan Wang
- Bethune First Hospital, Jilin University, Changchun, China
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Altunok TH, Muchut RJ, Iglesias AA, Yalcin A. Transforming growth factor β1 upregulates 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-4 expression in A549 and MCF-10A cells. Cell Biochem Funct 2023; 41:1220-1229. [PMID: 37707291 DOI: 10.1002/cbf.3856] [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: 07/13/2023] [Revised: 08/17/2023] [Accepted: 09/04/2023] [Indexed: 09/15/2023]
Abstract
Transforming growth factor β1 (TGFβ1) induces a cellular process known as epithelial-mesenchymal transition (EMT) associated with metabolic reprogramming, including enhanced glycolysis. Given the involvement of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFKFB) enzymes in glycolysis, we aimed to investigate whether TGFβ1 regulates expressions of PFKFB genes and if PFKFBs are required for TGFβ1-driven phenotypes. A549 and MCF-10A cell lines were used as TGFβ1-driven EMT models. Messenger RNA expressions of PFKFB and EMT genes were determined by real-time quantitative polymerase chain reaction. A small interfering RNA approach was used to deplete PFKFB4 expression. A Matrigel invasion assay was conducted to assess the effect of PFKFB4 silencing on the TGFβ1-enhanced invasion of A549 cells. F2,6BP levels were analyzed using an enzyme-coupled assay. Glucose and lactate concentrations were determined using colorimetric assays. TGFβ1 robustly induced expression of the fourth isoform of PFKFBs, PFKFB4, in both cell lines. PFKFB4 depletion partially inhibits mesenchymal transdifferentiation caused by TGFβ1 in A549 cells, as assessed by microscopy. Inductions of Snail in MCF-10A cells and Fibronectin in A549 cells and repressions of E-cadherin in both cell lines by TGFβ1 are attenuated by PFKFB4 silencing. PFKFB4 silencing reduces F2,6BP and glycolytic activity, although TGFβ1 alone does not affect these parameters. Finally, PFKFB4 depletion suppresses the TGFβ1-driven invasion of A549 cells through Matrigel. Presented data suggest that TGFβ1 induces the expression of PFKFB4 in A549 and MCF-10 cells, and PFKFB4 may be required for TGFβ1-driven phenotypes such as EMT and invasion in these models.
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Affiliation(s)
- Tugba H Altunok
- Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey
| | - Robertino J Muchut
- Department of Molecular Enzymology, Coastal Agrobiotechnology Institute, National University of Litoral, Santa Fe, Argentina
| | - Alberto A Iglesias
- Department of Molecular Enzymology, Coastal Agrobiotechnology Institute, National University of Litoral, Santa Fe, Argentina
| | - Abdullah Yalcin
- Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey
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12
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Zodda E, Tura-Ceide O, Mills NL, Tarragó-Celada J, Carini M, Thomson TM, Cascante M. Autonomous metabolic reprogramming and oxidative stress characterize endothelial dysfunction in acute myocardial infarction. eLife 2023; 12:e86260. [PMID: 38014932 PMCID: PMC10871716 DOI: 10.7554/elife.86260] [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: 01/18/2023] [Accepted: 08/01/2023] [Indexed: 11/29/2023] Open
Abstract
Compelling evidence has accumulated on the role of oxidative stress on the endothelial cell (EC) dysfunction in acute coronary syndrome. Unveiling the underlying metabolic determinants has been hampered by the scarcity of appropriate cell models to address cell-autonomous mechanisms of EC dysfunction. We have generated endothelial cells derived from thrombectomy specimens from patients affected with acute myocardial infarction (AMI) and conducted phenotypical and metabolic characterizations. AMI-derived endothelial cells (AMIECs) display impaired growth, migration, and tubulogenesis. Metabolically, AMIECs displayed augmented ROS and glutathione intracellular content, with a diminished glucose consumption coupled to high lactate production. In AMIECs, while PFKFB3 protein levels of were downregulated, PFKFB4 levels were upregulated, suggesting a shunting of glycolysis towards the pentose phosphate pathway, supported by upregulation of G6PD. Furthermore, the glutaminolytic enzyme GLS was upregulated in AMIECs, providing an explanation for the increase in glutathione content. Finally, AMIECs displayed a significantly higher mitochondrial membrane potential than control ECs, which, together with high ROS levels, suggests a coupled mitochondrial activity. We suggest that high mitochondrial proton coupling underlies the high production of ROS, balanced by PPP- and glutaminolysis-driven synthesis of glutathione, as a primary, cell-autonomous abnormality driving EC dysfunction in AMI.
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Affiliation(s)
- Erika Zodda
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of BarcelonaBarcelonaSpain
- Institute for Molecular Biology of Barcelona, National Research Council (IBMB-CSIC)BarcelonaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EDH)MadridSpain
| | - Olga Tura-Ceide
- Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS); University of BarcelonaBarcelonaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES)MadridSpain
- Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital de Girona, Santa Caterina Hospital de Salt and Girona Biomedical Research Institute (IDIBGI)GironaSpain
| | - Nicholas L Mills
- University/BHF Centre for Cardiovascular Science, University of EdinburghEdinburghUnited Kingdom
| | - Josep Tarragó-Celada
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of BarcelonaBarcelonaSpain
| | - Marina Carini
- Department of Pharmaceutical Sciences, Università degli Studi di MilanoMilanItaly
| | - Timothy M Thomson
- Institute for Molecular Biology of Barcelona, National Research Council (IBMB-CSIC)BarcelonaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EDH)MadridSpain
- Universidad Peruana Cayetano HerediaLimaPeru
| | - Marta Cascante
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of BarcelonaBarcelonaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EDH)MadridSpain
- Institute of Biomedicine (IBUB), University of BarcelonaBarcelonaSpain
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13
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Wang YH, Wang QT, Wu XT, Dong Y, Cui Q, Zhou YN, Yang XW, Lu WF, Li WY, Wang H, Zhao XD, Zhang M. Yiqi Yangjing recipe stimulates apoptosis while suppressing the energy metabolism via under-expression of PFKFB3 in A549 cells. J Thorac Dis 2023; 15:4885-4895. [PMID: 37868897 PMCID: PMC10586959 DOI: 10.21037/jtd-23-490] [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: 03/28/2023] [Accepted: 08/31/2023] [Indexed: 10/24/2023]
Abstract
Background Lung cancer is a malignant tumor associated with high morbidity and mortality. Yiqi Yangjing recipe (YYR) is a formula of traditional Chinese medicine (TCM) that is commonly used for the treatment of lung cancer with good clinical efficacy. The specific anti-cancer mechanism of YYR is still unknown. We need to embark on a more in-depth pharmacological study of YYR to determine the complex compound ingredients, which could be promoted in clinical practice to achieve efficacy in prolonging recurrent metastasis of lung cancer. Methods The cytotoxic effects of YYR on A549 cells were evaluated by Cell Counting Kit-8 (CCK-8) assay. The PFKFB3-under-expressed and overexpressed A549 cell lines were constructed via PFK15 treatment and transfection, respectively. The effects of YYR on PFKFB3 messenger RNA (mRNA) and protein expression were detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. The pro-apoptotic and anti-glycolytic abilities of YYR were measured using flow cytometry assay and hippocampal XF96 extracellular flux analyzer. An in vivo tumorigenicity assay was performed on nude mice to confirm the anti-cancer effects of YYR. Results YYR has a noticeable cytotoxic activity on A549 cells, with the treatment with both YYR and PFK15 significantly inducing apoptosis. YYR and PFK15 treatment reduced the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in A549 cells. Similar to PFK15, YYR can down-regulate PFKFB3 expression, and PFKFB3 overexpression suppressed the apoptosis, which was reversed by YYR. Animal experiments confirmed that YYR was able to inhibit tumor growth, induce tumor cell apoptosis, and down-regulate PFKFB3 in tumor tissues. Conclusions This study demonstrated that YYR promoted lung cancer cell apoptosis and inhibited energy metabolism by targeting PFKFB3. Furthermore, we believe that YYR may be a suitable supplement or alternative drug for lung cancer treatment.
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Affiliation(s)
- Yu-Han Wang
- Department of Integrated Traditional Chinese and Western Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing-Ting Wang
- Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Ting Wu
- Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yun Dong
- Department of Integrated Traditional Chinese and Western Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Cui
- Department of Integrated Traditional Chinese and Western Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ya-Ning Zhou
- Department of Integrated Traditional Chinese and Western Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xi-Wen Yang
- Shanghai Literature Institute of Traditional Chinese Medicine, Shanghai, China
| | - Wen-Feng Lu
- Department of Integrated Traditional Chinese and Western Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wan-Yu Li
- Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Wang
- Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Dong Zhao
- Shanghai Center for Systems Biomedicines, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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14
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Kashyap A, Umar SM, Dev J R A, Mathur SR, Gogia A, Batra A, Deo SVS, Prasad CP. Combination of 3PO analog PFK15 and siPFKL efficiently suppresses the migration, colony formation ability, and PFK-1 activity of triple-negative breast cancers by reducing the glycolysis. J Cell Biochem 2023; 124:1259-1272. [PMID: 37450687 DOI: 10.1002/jcb.30443] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 04/14/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023]
Abstract
Among all the subtypes of breast cancer, triple-negative breast cancer (TNBC) has been associated with the worst prognosis. Recently, for many solid tumors (including breast cancer) metabolic reprogramming has appeared as a cancer cell hallmark, and the elevated glycolytic pathway has been linked to their aggressive phenotype. In the present study, we evaluated the prognostic and therapeutic relevance of PFKFB3 (6-phosphofructo-2- kinase/fructose-2,6-bisphosphatase) in TNBCs. Prognostic significance of PFKFB3 expression was evaluated in overall breast cancers as well as in TNBCs. PFKFB3 inhibitor (3PO potent analogue i.e., PFK15) cytotoxicity in TNBC cell lines (MDA-MB-231 and MDA-MB-468) was analyzed using an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cancer cell physiological characteristics like clonogenicity and migration were also investigated after PFK15 treatment. As fructose-2,6-bisphosphate (F-2,6-BP), has been associated with increased PFK-1 activity, the effect of PFKFB3 inhibition by PFK15 was investigated on two major isoforms of phosphofructokinase-1 (PFK-1) in breast cancer, that is, phosphofructokinase-platelet type (PFKP) and phosphofructokinase-liver type (PFKL) (relevant to breast cancer). For PFKL inhibition, the siRNA approach was used. PFKFB3 expression was significantly correlated with inferior overall survival in breast cancer patients including TNBCs. PFK15 treatment in TNBC cells (i.e., MDA-MB-231 and MDA-MB-468) resulted in a decreased PFKP expression, thereby leading to reduced colony formation ability, migration rate, and extracellular lactate levels. However, to our surprise PFK15 treatment in both TNBC cells also resulted in elevated PFKL levels. Our results demonstrated that the combinatorial inhibition of PFK15 with siPFKL was more effective in TNBC cells, as it led to a decrease in colony formation ability, migration rate, extracellular lactate levels, and PFK-1 activity when compared with individual treatments. Using bona fide PFKFB3 inhibitor, that is, AZ67, we further show that AZ67 treatment to TNBC cells has no effect either on the expression of PFKP and PFKL, or on the lactate production. In summary, our present in vitro study demonstrated that 3PO derived PFK15 mechanism of action is totally different from AZ67 in TNBC cells. However, we advocate that the PFK15-mediated inhibition (along with PFKL) on the TNBCs migration, colony formation, and PFK-1 activity can be further explored for the therapeutic advantage of TNBC patients.
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Affiliation(s)
- Akanksha Kashyap
- Department of Medical Oncology (Laboratory), Dr. BRA IRCH, AIIMS, New Delhi, India
| | - Sheikh Mohammad Umar
- Department of Medical Oncology (Laboratory), Dr. BRA IRCH, AIIMS, New Delhi, India
| | - Arundhathi Dev J R
- Department of Medical Oncology (Laboratory), Dr. BRA IRCH, AIIMS, New Delhi, India
| | | | - Ajay Gogia
- Department of Medical Oncology, Dr. BRA IRCH, AIIMS, New Delhi, India
| | - Atul Batra
- Department of Medical Oncology, Dr. BRA IRCH, AIIMS, New Delhi, India
| | - S V S Deo
- Department of Surgical Oncology, Dr. BRA IRCH, AIIMS, New Delhi, India
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15
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Wu Y, Kou Q, Sun L, Hu X. Effects of anoxic prognostic model on immune microenvironment in pancreatic cancer. Sci Rep 2023; 13:9104. [PMID: 37277450 PMCID: PMC10241784 DOI: 10.1038/s41598-023-36413-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 06/03/2023] [Indexed: 06/07/2023] Open
Abstract
Pancreatic cancer has one of the worst prognoses in the world, which suggests that the tumor microenvironment, which is characterized by hypoxia and immunosuppression, plays a significant role in the prognosis and progression of pancreatic cancer. We identified PLAU, LDHA, and PKM as key genes involved in pancreatic cancer hypoxia through GO/KEGG enrichment related hypoxia pathways and cox regression, established prognostic models, and studied their relationship to immune invasion through bioinformatics using R and related online databases. We verified the high expression of PLAU, LDHA, and PKM in pancreatic cancer cells using qPCR in vitro, and we also discovered that the expression of PLAU, LDHA, and PKM in hypoxic pancreatic cancer cells differed from that in normal cultured pancreatic cancer cells. Finally, we discovered that our prognostic model accurately predicted postrain in pancreatic cancer patients with hypoxia and immune infiltration.
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Affiliation(s)
- Yangdong Wu
- Department of Hepatobiliary Pancreatic Surgery, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong, People's Republic of China
| | - Qingyan Kou
- Department of Hepatobiliary Pancreatic Surgery, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong, People's Republic of China
| | - Lin Sun
- Department of ICU, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiao Hu
- Department of Hepatobiliary Pancreatic Surgery, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, Shandong, People's Republic of China.
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16
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Alizadeh J, Kavoosi M, Singh N, Lorzadeh S, Ravandi A, Kidane B, Ahmed N, Mraiche F, Mowat MR, Ghavami S. Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer. Cancers (Basel) 2023; 15:2195. [PMID: 37190124 PMCID: PMC10136996 DOI: 10.3390/cancers15082195] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/21/2023] [Accepted: 03/28/2023] [Indexed: 05/17/2023] Open
Abstract
Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer.
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Affiliation(s)
- Javad Alizadeh
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Mahboubeh Kavoosi
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Navjit Singh
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Amir Ravandi
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Institute of Cardiovascular Sciences, Albrechtsen Research Centre, St. Boniface Hospital, Winnipeg, MB R2H 2A6, Canada;
| | - Biniam Kidane
- Section of Thoracic Surgery, Department of Surgery, Health Sciences Centre, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 6C5, Canada;
- CancerCare Manitoba Research Institute, Winnipeg, MB R3E 0V9, Canada; (N.A.)
| | - Naseer Ahmed
- CancerCare Manitoba Research Institute, Winnipeg, MB R3E 0V9, Canada; (N.A.)
- Department of Radiology, Section of Radiation Oncology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Fatima Mraiche
- College of Pharmacy, QU Health, Qatar University, Doha 2713, Qatar;
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Michael R. Mowat
- CancerCare Manitoba Research Institute, Winnipeg, MB R3E 0V9, Canada; (N.A.)
- Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
- Research Institute of Oncology and Hematology, Winnipeg, MB R3E 0V9, Canada
- Faculty of Medicine in Zabrze, Academia of Silesia, 41-800 Zabrze, Poland
- Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 3P5, Canada
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17
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Sittewelle M, Kappès V, Zhou C, Lécuyer D, Monsoro-Burq AH. PFKFB4 interacts with ICMT and activates RAS/AKT signaling-dependent cell migration in melanoma. Life Sci Alliance 2022; 5:5/12/e202201377. [PMID: 35914811 PMCID: PMC9348664 DOI: 10.26508/lsa.202201377] [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: 01/20/2022] [Revised: 07/04/2022] [Accepted: 07/06/2022] [Indexed: 11/24/2022] Open
Abstract
Glycolysis regulator PFKFB4 promotes cell migration in metastatic melanoma and normal melanocytes by a non-conventional glycolysis-independent function involving ICMT, RAS, and AKT signaling. Cell migration is a complex process, tightly regulated during embryonic development and abnormally activated during cancer metastasis. RAS-dependent signaling is a major nexus controlling essential cell parameters including proliferation, survival, and migration, utilizing downstream effectors such as the PI3K/AKT signaling pathway. In melanoma, oncogenic mutations frequently enhance RAS, PI3K/AKT, or MAP kinase signaling and trigger other cancer hallmarks among which the activation of metabolism regulators. PFKFB4 is one of these critical regulators of glycolysis and of the Warburg effect. Here, however, we explore a novel function of PFKFB4 in melanoma cell migration. We find that PFKFB4 interacts with ICMT, a posttranslational modifier of RAS. PFKFB4 promotes ICMT/RAS interaction, controls RAS localization at the plasma membrane, activates AKT signaling and enhances cell migration. We thus provide evidence of a novel and glycolysis-independent function of PFKFB4 in human cancer cells. This unconventional activity links the metabolic regulator PFKFB4 to RAS-AKT signaling and impacts melanoma cell migration.
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Affiliation(s)
- Méghane Sittewelle
- Université Paris-Saclay, Faculté des Sciences d'Orsay, CNRS UMR 3347, INSERM U1021, Orsay, France.,Institut Curie Research Division, PSL Research University, CNRS UMR 3347, INSERM U1021, Orsay, France
| | - Vincent Kappès
- Université Paris-Saclay, Faculté des Sciences d'Orsay, CNRS UMR 3347, INSERM U1021, Orsay, France.,Institut Curie Research Division, PSL Research University, CNRS UMR 3347, INSERM U1021, Orsay, France
| | - Chenxi Zhou
- Université Paris-Saclay, Faculté des Sciences d'Orsay, CNRS UMR 3347, INSERM U1021, Orsay, France.,Institut Curie Research Division, PSL Research University, CNRS UMR 3347, INSERM U1021, Orsay, France
| | - Déborah Lécuyer
- Université Paris-Saclay, Faculté des Sciences d'Orsay, CNRS UMR 3347, INSERM U1021, Orsay, France.,Institut Curie Research Division, PSL Research University, CNRS UMR 3347, INSERM U1021, Orsay, France
| | - Anne H Monsoro-Burq
- Université Paris-Saclay, Faculté des Sciences d'Orsay, CNRS UMR 3347, INSERM U1021, Orsay, France .,Institut Curie Research Division, PSL Research University, CNRS UMR 3347, INSERM U1021, Orsay, France
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18
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Lv L, Huang RH, Li J, Xu J, Gao W. Impact of NSCLC metabolic remodeling on immunotherapy effectiveness. Biomark Res 2022; 10:66. [PMID: 36038935 PMCID: PMC9425942 DOI: 10.1186/s40364-022-00412-1] [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: 05/31/2022] [Accepted: 08/12/2022] [Indexed: 11/10/2022] Open
Abstract
It is known that metabolic reprogramming (MR) contributes to tumorigenesis through the activation of processes that support survival of cells, proliferation, and grow in the tumor microenvironment. In order to keep the tumor proliferating at a high rate, metabolic pathways must be upregulated, and tumor metabolism must be adapted to meet this requirement. Additionally, immune cells engage in metabolic remodeling to maintain body and self-health. With the advent of immunotherapy, the fate of individuals suffering from non-small cell lung cancer (NSCLC) has been transformed dramatically. MR may have a profound influence on their prognosis. The aim of this review is to summarize current research advancements in metabolic reprogramming and their impact on immunotherapy in NSCLC. Moreover, we talk about promising approaches targeting and manipulating metabolic pathways to improve cancer immunotherapy’s effectiveness in NSCLC.
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Affiliation(s)
- Lulu Lv
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Ruo Han Huang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Jiale Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Jing Xu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
| | - Wen Gao
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
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19
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Gong Y, Liu X, Sahu A, Reddy AV, Wang H. Exploration of hub genes, lipid metabolism, and the immune microenvironment in stomach carcinoma and cholangiocarcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:834. [PMID: 36034995 PMCID: PMC9403925 DOI: 10.21037/atm-22-3530] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/02/2022] [Indexed: 01/11/2023]
Abstract
Background Gastric cancer (GC) is the 5th most common cause of cancer in the world and the 3rd largest cause of cancer-related death. It is usually associated with a variety of cancers, of which cholangiocarcinoma (CCA) combined with GC accounts for about 1.6%. This study sought to examine the hub genes and role of lipid metabolism in the development and diagnosis of GC and CCA. Methods To screen potential hub genes, The Cancer Genome Atlas (TCGA) data sets, including the GC (STAD, dataset of GC) and CCA (CHOL, dataset of CCA) data sets, were used to conduct a differentially expressed gene (DEG) analysis and an enrichment analysis of the DEGs. A weighted-gene co-expression network analysis (WGCNA) was conducted to identify the significant gene module and then find the hub genes in the module. To verify the 4 hub genes, we conducted a differentiation analysis of the 4 genes in GC and CCA and found that there were differences. A survival analysis of the hub genes was performed and mutations were mapped. Additionally, tumor immune microenvironment (TIME) and immune analyses were performed to evaluate how lipid metabolism affects the development of GC with CCA. Results The principal component analysis showed that both GC and CCA had distinct up-regulated and down-regulated genes, which are involved in a variety of metabolic processes. Upon WGCNA, the turquoise and blue modules were meaningful, and the hub genes were identified from these 2 modules. Four hub genes were identified: amyloid beta precursor protein binding family B member 1 (APBB1), Homo sapiens armadillo repeat containing X-linked 1 (ARMCX1), DAZ interacting zinc finger protein 1 (DZIP1), and methionine sulfoxide reductase B3 (MSRB3). In survival analysis, increased expression of the 4 hub genes was associated with inferior survival outcomes, with variations in all 4 genes. Additionally, we demonstrated that genes related to lipid metabolism had an effect on immune function. Conclusions APBB1, ARMCX1, DZIP1, and MSRB3 affect the development of GC and CCA and can be used as biomarkers. The expression of lipid metabolism genes is related to the TIME of patients with GC and CCA.
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Affiliation(s)
- Yuda Gong
- Department of General Surgery, Fudan University Zhongshan Hospital, Shanghai, China
| | - Xuan Liu
- Department of General Surgery, Fudan University Zhongshan Hospital, Shanghai, China
| | - Arvind Sahu
- Department of Oncology, Goulburn Valley Health, Shepparton, Victoria, Australia
| | - Abhinav V Reddy
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Sidney Kimmel Cancer Center, Baltimore, MD, USA
| | - Haiyu Wang
- Department of General Surgery, Fudan University Zhongshan Hospital, Shanghai, China
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20
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PFKFB3 regulates cancer stemness through the hippo pathway in small cell lung carcinoma. Oncogene 2022; 41:4003-4017. [PMID: 35804016 PMCID: PMC9374593 DOI: 10.1038/s41388-022-02391-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 12/16/2022]
Abstract
PFKFB3 (6-phosphofructo-2-kinase) is the rate-limiting enzyme of glycolysis and is overexpressed in several human cancers that are associated with poor prognosis. High PFKFB3 expression in cancer stem cells promotes glycolysis and survival in the tumor microenvironment. Inhibition of PFKFB3 by the glycolytic inhibitor PFK158 and by shRNA stable knockdown in small cell lung carcinoma (SCLC) cell lines inhibited glycolysis, proliferation, spheroid formation, and the expression of cancer stem cell markers CD133, Aldh1, CD44, Sox2, and ABCG2. These factors are also associated with chemotherapy resistance. We found that PFK158 treatment and PFKFB3 knockdown enhanced the ABCG2-interacting drugs doxorubicin, etoposide, and 5-fluorouracil in reducing cell viability under conditions of enriched cancer stem cells (CSC). Additionally, PFKFB3 inhibition attenuated the invasion/migration of SCLC cells by downregulating YAP/TAZ signaling while increasing pLATS1 via activation of pMST1 and NF2 and by reducing the mesenchymal protein expression. PFKFB3 knockdown and PFK158 treatment in a H1048 SCLC cancer stem cell-enriched mouse xenograft model showed significant reduction in tumor growth and weight with reduced expression of cancer stem cell markers, ABCG2, and YAP/TAZ. Our findings identify that PFKFB3 is a novel target to regulate cancer stem cells and its associated therapeutic resistance markers YAP/TAZ and ABCG2 in SCLC models.
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21
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Altered Transcriptional Regulation of Glycolysis in Circulating CD8+ T Cells of Rheumatoid Arthritis Patients. Genes (Basel) 2022; 13:genes13071216. [PMID: 35886000 PMCID: PMC9323564 DOI: 10.3390/genes13071216] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 12/04/2022] Open
Abstract
Peripheral T lymphocytes of rheumatoid arthritis (RA) patients show pathological changes in their metabolic pathways, especially glycolysis. These changes may drive the increased proliferation and tissue invasiveness of RA T cells. In order to study the transcriptional regulation underlying these alterations, we analysed publicly available RNA sequencing data from circulating T lymphocyte subsets of healthy individuals, untreated RA patients, and patients undergoing treatment for RA. Differential co-expression networks were created using sample-wise edge weights from an analysis called “linear interpolation to obtain network estimates for single sample” (lionessR), and annotated using the Gene Transcription Regulation Database (GTRD). Genes with high centrality scores were identified. CD8+ effector memory cells (Tem) and CD8+CD45RA+ effector memory cells (Temra) showed large changes in the transcriptional regulation of glycolysis in untreated RA. PFKFB3 and GAPDH were differentially regulated and had high centrality scores in CD8+ Tem cells. PFKFB3 downregulation may be due to HIF1A post transcriptional inhibition. Tocilizumab treatment partially reversed the RA-associated differential expression of several metabolic and regulatory genes. MYC was upregulated and had high centrality scores in RA CD8+ Temra cells; however, its glycolysis targets were unaltered. The upregulation of the PI3K-AKT and mTOR pathways may explain MYC upregulation.
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22
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Wang W, Wang B. KDM3A-mediated SP1 activates PFKFB4 transcription to promote aerobic glycolysis in osteosarcoma and augment tumor development. BMC Cancer 2022; 22:562. [PMID: 35590288 PMCID: PMC9118730 DOI: 10.1186/s12885-022-09636-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 05/05/2022] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Lysine-specific histone demethylase 3A (KDM3A) is a potent histone modifier that is frequently implicated in the progression of several malignancies. However, its role in aerobic glycolysis of osteosarcoma (OS) remains unclear. METHODS KDM3A expression in OS tissues was determined by immunohistochemistry, and that in acquired OS cells was determined by RT-qPCR and western blot assays. KDM3A was silenced in OS cells to examine cellular behaviors and the aerobic glycolysis. Stably transfected cells were injected into nude mice for in vivo experiments. The downstream targets of KDM3A were predicted by bioinformatics systems and validated by ChIP-qPCR. Rescue experiments of SP1 and PFKFB4 were performed to examine their roles in the KDM3A-mediated events. RESULTS KDM3A was highly expressed in OS tissues and cells. Knockdown of KDM3A weakened OS cell growth and metastasis in vivo and in vitro, and it suppressed the aerobic glycolysis in OS cells. KDM3A enhanced the transcription of SP1 by demethylating H3K9me2 on its promoter. Restoration of SP1 rescued growth and metastasis of OS cells and recovered the glycolytic flux in cells suppressed by knockdown of KDM3A. SP1 bound to the PFKFB4 promoter to activate its transcription and expression. PFKFB4 expression in OS cells was suppressed by KDM3A silencing but increased after SP1 restoration. Overexpression of PFKFB4 significantly promoted OS cell growth and metastasis as well as the glycolytic flux in cells. CONCLUSION This paper elucidates that upregulation of PFKFB4 mediated by the KDM3A-SP1 axis promotes aerobic glycolysis in OS and augments tumor development.
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Affiliation(s)
- Wei Wang
- Department of Orthopedics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110000, Liaoning, P.R. China
| | - Bin Wang
- Department of Orthopedics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110000, Liaoning, P.R. China.
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23
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Wang W, Zhou L, Li Z, Lin G. Circ_0014130 is involved in the drug sensitivity of colorectal cancer through miR-197-3p/PFKFB3 axis. J Gastroenterol Hepatol 2022; 37:908-918. [PMID: 35288979 DOI: 10.1111/jgh.15829] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 01/18/2022] [Accepted: 03/04/2022] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIM Colorectal cancer (CRC) is one of the most deadly cancers in the world, with few treatments and a poor prognosis. In recent years, many circular RNAs have been studied in CRC, but the role of circ_0014130 in CRC has not been investigated. Therefore, this research is designed to investigate the impact of circ_0014130 on the resistance of 5-fluorouracil (5-FU) in CRC. METHODS Quantitative real-time polymerase chain reaction was conducted to assess the expression of circ_0014130, microRNA-197-3p (miR-197-3p), and 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3). The expression of PFKFB3 protein was detected by Western blot. The effect of cric_0014130 on drug resistance in CRC was verified by Cell Counting Kit-8 assay, clone formation assay, Transwell, and flow cytometry. The effect of circ_0014130 on tumor growth was evaluated by xenograft tumor model in vivo. RESULTS Circ_0014130 and PFKFB3 were increased, while miR-197-3p was reversed in CRC tissues and cells. Knocking down circ_0014130 can promote cell apoptosis, inhibit the proliferation of CRC cells, and reduced the IC50 of 5-FU. In addition, miR-197-3p inhibitors reversed the effect of si-circ_0014130 on CRC cells. Similarly, overexpression of PFKFB3 can regulate CRC cell behavior and 5-FU resistance caused by miR-197-3p. Finally, decrease of circ_0014130 was demonstrated to enhance the resistance of 5-FU in CRC tissues in vivo. CONCLUSION Circ_0014130 modulates 5-FU resistance in CRC by modulating the miR-197-3p/PFKFB3 axis, which is helpful for drug chemotherapy in CRC.
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Affiliation(s)
- Wei Wang
- Department of Integrated Traditional Chinese and Western Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Lijiang Zhou
- Department of Oncology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
| | - Zheng Li
- Department of Integrated Traditional Chinese and Western Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Guanhong Lin
- Department of Integrated Traditional Chinese and Western Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
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Jones BC, Pohlmann PR, Clarke R, Sengupta S. Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux. Cancer Metastasis Rev 2022; 41:447-458. [PMID: 35419769 DOI: 10.1007/s10555-022-10027-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 03/16/2022] [Indexed: 12/11/2022]
Abstract
Reprogrammed metabolism and high energy demand are well-established properties of cancer cells that enable tumor growth. Glycolysis is a primary metabolic pathway that supplies this increased energy demand, leading to a high rate of glycolytic flux and a greater dependence on glucose in tumor cells. Finding safe and effective means to control glycolytic flux and curb cancer cell proliferation has gained increasing interest in recent years. A critical step in glycolysis is controlled by the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which converts fructose 6-phosphate (F6P) to fructose 2,6-bisphosphate (F2,6BP). F2,6BP allosterically activates the rate-limiting step of glycolysis catalyzed by PFK1 enzyme. PFKFB3 is often overexpressed in many human cancers including pancreatic, colon, prostate, and breast cancer. Hence, PFKFB3 has gained increased interest as a compelling therapeutic target. In this review, we summarize and discuss the current knowledge of PFKFB3 functions, its role in cellular pathways and cancer development, its transcriptional and post-translational activity regulation, and the multiple pharmacologic inhibitors that have been used to block PFKFB3 activity in cancer cells. While much remains to be learned, PFKFB3 continues to hold great promise as an important therapeutic target either as a single agent or in combination with current interventions for breast and other cancers.
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Affiliation(s)
- Brandon C Jones
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, 3970 Reservoir Rd NW, Washington, DC, 20057, USA
| | - Paula R Pohlmann
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1354, Houston, TX, 77030, USA
| | - Robert Clarke
- The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN, 55912, USA
| | - Surojeet Sengupta
- The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN, 55912, USA.
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Zhang Z, Zhang HJ. Glycometabolic rearrangements-aerobic glycolysis in pancreatic ductal adenocarcinoma (PDAC): roles, regulatory networks, and therapeutic potential. Expert Opin Ther Targets 2021; 25:1077-1093. [PMID: 34874212 DOI: 10.1080/14728222.2021.2015321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Glycometabolic rearrangements (aerobic glycolysis) is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumorigenesis and progression through numerous mechanisms. The targeting of aerobic glycolysis is recognized as a potential therapeutic strategy which offers the possibility of improving treatment outcomes for PDAC patients. AREAS COVERED In this review, the role of aerobic glycolysis and its regulatory networks in PDAC are discussed. The targeting of aerobic glycolysis in PDAC is examined, and its therapeutic potential is evaluated. The relevant literature published from 2001 to 2021 was searched in databases including PubMed, Scopus, and Embase. EXPERT OPINION Regulatory networks of aerobic glycolysis in PDAC are based on key factors such as c-Myc, hypoxia-inducible factor 1α, the mammalian target of rapamycin pathway, and non-coding RNAs. Experimental evidence suggests that modulators or inhibitors of aerobic glycolysis promote therapeutic effects in preclinical tumor models. Nevertheless, successful clinical translation of drugs that target aerobic glycolysis in PDAC is an obstacle. Moreover, it is necessary to identify the potential targets for future interventions from regulatory networks to design efficacious and safer agents.
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Affiliation(s)
- Zhong Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, People's Republic of China
| | - Hai-Jun Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, People's Republic of China
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Xing J, Jia Z, Xu Y, Chen M, Yang Z, Chen Y, Han Y. KLF9 (Kruppel Like Factor 9) induced PFKFB3 (6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3) downregulation inhibits the proliferation, metastasis and aerobic glycolysis of cutaneous squamous cell carcinoma cells. Bioengineered 2021; 12:7563-7576. [PMID: 34612136 PMCID: PMC8806463 DOI: 10.1080/21655979.2021.1980644] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer in humans with increasing incidence. In this paper, we focused on the effects of krueppel-like factor 9 (KLF9) on the progression of CSCC cells by binding to PFKFB3. mRNA and protein expressions of KLF9 and PFKFB3 in human HaCaT and CSCC cells were, respectively, examined by RT-qPCR analysis and Western blot. The viability, proliferation, invasion and migration of A431 cells after transfection were analyzed with MTT, clone formation, transwell and wound healing assays. The levels of glucose, lactic acid and ATP in transfected A431 cells were detected by their commercial kits. Ki-67 expression in transfected A431 cells was determined using immunofluorescence analysis and in tumor tissues was analyzed by immunohistochemistry. The levels of migration, EMT and aerobic glycolysis-related proteins were tested with Western blot. The combination of KLF9 and PFKFB3 was confirmed by dual-luciferase reporter assay and ChIP. As a result, PFKFB3 expression was elevated in CSCC cells compared with HaCaT. Knockdown of PFKFB3 restrained the proliferation, metastasis, and aerobic glycolysis of CSCC cells. In addition, KLF9 could bind to PFKFB3. Downregulation of KLF9 crippled the inhibitory effect of knockdown of PFKFB3 on the proliferation, metastasis, and aerobic glycolysis of CSCC cells. In conclusion, PFKFB3 was transcriptionally regulated by KLF9, and PFKFB3 silencing inhibits the proliferation, metastasis, and aerobic glycolysis of cutaneous squamous cell carcinoma cells.
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Affiliation(s)
- Jiahua Xing
- Department of Plastic and Reconstructive Surgery, The First Medical Center, Chinese Pla General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Ziqi Jia
- Peking Union Medical College, Beijing, China
| | - Yichi Xu
- Department of Plastic and Reconstructive Surgery, The First Medical Center, Chinese Pla General Hospital, Beijing, China
| | - Muzi Chen
- Department of Plastic and Reconstructive Surgery, The First Medical Center, Chinese Pla General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Zheng Yang
- Department of Plastic and Reconstructive Surgery, The First Medical Center, Chinese Pla General Hospital, Beijing, China
| | - Youbai Chen
- Department of Plastic and Reconstructive Surgery, The First Medical Center, Chinese Pla General Hospital, Beijing, China
| | - Yan Han
- Department of Plastic and Reconstructive Surgery, The First Medical Center, Chinese Pla General Hospital, Beijing, China
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27
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Liu C, Jin Y, Fan Z. The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer. Front Oncol 2021; 11:698023. [PMID: 34540667 PMCID: PMC8446599 DOI: 10.3389/fonc.2021.698023] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 08/11/2021] [Indexed: 12/26/2022] Open
Abstract
Although chemotherapy can improve the overall survival and prognosis of cancer patients, chemoresistance remains an obstacle due to the diversity, heterogeneity, and adaptability to environmental alters in clinic. To determine more possibilities for cancer therapy, recent studies have begun to explore changes in the metabolism, especially glycolysis. The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes to chemoresistance. However, the association between glycolysis and chemoresistance and molecular mechanisms of glycolysis-induced chemoresistance remains unclear. This review describes the mechanism of glycolysis-induced chemoresistance from the aspects of glycolysis process, signaling pathways, tumor microenvironment, and their interactions. The understanding of how glycolysis induces chemoresistance may provide new molecular targets and concepts for cancer therapy.
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Affiliation(s)
- Chang Liu
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China
| | - Ying Jin
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China
| | - Zhimin Fan
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China
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28
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Shevchenko NS, Krutenko NV, Zimnytska TV, Voloshyn KV. The role of hypoxia-inducible factors in the development of chronic pathology. UKRAINIAN BIOCHEMICAL JOURNAL 2021. [DOI: 10.15407/ubj93.04.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
This review highlights the current understanding of hypoxia-inducible factors (HIFs) role as regulators of oxygen-dependent reactions and inducers of genes expression in human organism. The focus is on the most significant relationships between the activation or inhibition of the HIFs intracellular system and development of the inflammatory process in various organs, chronic diseases of gastrointestinal tract, osteoarticular system, kidneys as well as hematological, endocrine and metabolic disorders.
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29
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Estaras M, Gonzalez A. Modulation of cell physiology under hypoxia in pancreatic cancer. World J Gastroenterol 2021; 27:4582-4602. [PMID: 34366624 PMCID: PMC8326256 DOI: 10.3748/wjg.v27.i28.4582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/28/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
In solid tumors, the development of vasculature is, to some extent, slower than the proliferation of the different types of cells that form the tissue, both cancer and stroma cells. As a consequence, the oxygen availability is compromised and the tissue evolves toward a condition of hypoxia. The presence of hypoxia is variable depending on where the cells are localized, being less extreme at the periphery of the tumor and more severe in areas located deep within the tumor mass. Surprisingly, the cells do not die. Intracellular pathways that are critical for cell fate such as endoplasmic reticulum stress, apoptosis, autophagy, and others are all involved in cellular responses to the low oxygen availability and are orchestrated by hypoxia-inducible factor. Oxidative stress and inflammation are critical conditions that develop under hypoxia. Together with changes in cellular bioenergetics, all contribute to cell survival. Moreover, cell-to-cell interaction is established within the tumor such that cancer cells and the microenvironment maintain a bidirectional communication. Additionally, the release of extracellular vesicles, or exosomes, represents short and long loops that can convey important information regarding invasion and metastasis. As a result, the tumor grows and its malignancy increases. Currently, one of the most lethal tumors is pancreatic cancer. This paper reviews the most recent advances in the knowledge of how cells grow in a pancreatic tumor by adapting to hypoxia. Unmasking the physiological processes that help the tumor increase its size and their regulation will be of major relevance for the treatment of this deadly tumor.
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Affiliation(s)
- Matias Estaras
- Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, Caceres 10003, Spain
| | - Antonio Gonzalez
- Department of Physiology, Cell Biology and Communication Research Group, University of Extremadura, Caceres 10003, Spain
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30
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Sha L, Lv Z, Liu Y, Zhang Y, Sui X, Wang T, Zhang H. Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer. Mol Med Rep 2021; 24:560. [PMID: 34109434 PMCID: PMC8201656 DOI: 10.3892/mmr.2021.12199] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 02/04/2021] [Indexed: 01/24/2023] Open
Abstract
Lung cancer is one of the most lethal diseases and therefore poses a significant threat to human health. The Warburg effect, which is the observation that cancer cells predominately produce energy through glycolysis, even under aerobic conditions, is a hallmark of cancer. 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB) is an important regulator of glycolysis. Shikonin is a Traditional Chinese herbal medicine, which has been reported to exert antitumor effects. The present study aimed to investigate the anticancer activity of shikonin in lung cancer. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to analyze proliferation in A549 and H446 cells. Wound healing and Transwell assays were used to measure migration and invasion in A549 and H446 cells. Cell apoptosis was analyzed using flow cytometry. Lactate levels, glucose uptake and cellular ATP levels were measured using their corresponding commercial kits. Western blotting was performed to analyze the protein expression levels of key enzymes involved in aerobic glucose metabolism. Reverse transcription-quantitative PCR was used to analyze the mRNA expression levels of PFKFB2. The results of the present study revealed that PFKFB2 expression levels were significantly upregulated in NSCLC tissues. Shikonin treatment decreased the proliferation, migration, invasion, glucose uptake, lactate levels, ATP levels and PFKFB2 expression levels and increased apoptosis in lung cancer cells in a dose-dependent manner. The overexpression of PFKFB2 increased the proliferation, migration, glucose uptake, lactate levels and ATP levels in lung cancer cells, while the knockdown of PFKFB2 expression exerted the opposite effects. Moreover, there were no significant differences in lung cancer cell migration, apoptosis, glucose uptake, lactate levels and ATP levels between cells with knocked down PFKFB2 expression or treated with shikonin and the knockdown of PFKFB2 in cells treated with shikonin. In conclusion, the results of the present study revealed that shikonin inhibited the Warburg effect and exerted antitumor activity in lung cancer cells, which was associated with the downregulation of PFKFB2 expression.
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Affiliation(s)
- Liying Sha
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Zhiqiang Lv
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Yujun Liu
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Yun Zhang
- Department of Business, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Xin Sui
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Teng Wang
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Hui Zhang
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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Identification of differentially expressed genes and the role of PDK4 in CD14+ monocytes of coronary artery disease. Biosci Rep 2021; 41:228119. [PMID: 33739370 PMCID: PMC8024870 DOI: 10.1042/bsr20204124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 02/22/2021] [Accepted: 03/17/2021] [Indexed: 12/28/2022] Open
Abstract
Background. Coronary artery disease (CAD) is a chronic inflammatory disease caused by development of atherosclerosis (AS), which is the leading cause of mortality and disability. Our study aimed to identify the differentially expressed genes (DEGs) in CD14+ monocytes from CAD patients compared with those from non-CAD controls, which might pave the way to diagnosis and treatment for CAD. Methods. The RNA-sequencing (RNA-seq) was performed by BGISEQ-500, followed by analyzing with R package to screening DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed by R package. In addition, we validated the results of RNA-seq using real-time quantitative polymerase chain reaction (RT-qPCR). Furthermore, we explored the function of selected ten genes in LDL-treated CD14+ monocytes by RT-qPCR. Results. a total of 2897 DEGs were identified, including 753 up- and 2144 down-regulated genes in CD14+ monocytes from CAD patients. These DEGs were mainly enriched in plasma membrane and cell periphery of cell component, immune system process of biological process, NF-κB signaling pathway, cell adhesion molecules signaling pathway and cytokine–cytokine receptor interaction signaling pathway. In LDL-treated CD14+ monocytes, the mRNA expression of pyruvate dehydrogenase kinase 4 (PDK4) was significantly up-regulated. Conclusion. In the present study, we suggested that PDK4 might play a role in progression of CAD. The study will provide some pieces of evidence to investigate the role and mechanism of key genes in the pathogenesis of CAD.
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32
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Lu C, Qiao P, Sun Y, Ren C, Yu Z. Positive regulation of PFKFB3 by PIM2 promotes glycolysis and paclitaxel resistance in breast cancer. Clin Transl Med 2021; 11:e400. [PMID: 33931981 PMCID: PMC8087946 DOI: 10.1002/ctm2.400] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 04/07/2021] [Accepted: 04/12/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Breast cancer (BC) is one of the most common female malignancies in the world. Chemotherapeutic resistance is the major cause of BC therapy failure, leading to tumor recurrence and metastasis. Studies have illustrated the close relationship between glycolysis and BC progression and drug resistance. The key glycolysis regulator, PFKFB3 makes a difference during BC progression and drug resistance. However, the mechanism remains to be unknown. METHODS Mass spectrometry analyses were used to found that PIM2 was a potential new binding protein of PFKFB3. Co-immunoprecipitated and western blot were used to verify the interaction between PIM2 and PFKFB3 in BC and the molecular mechanism by which PIM2 phosphorylates PFKFB3 in regulating the protein function. PFKFB3 mutant forms were used to demonstrate the need for PFKFB3 in BC drug resistance. RESULTS We identified that PIM2 is a new binding protein of PFKFB3. We used biochemical methods to determine that PIM2 can directly bind and change the phosphorylation of PFKFB3 at Ser478 to enhance PFKFB3 protein stability through the ubiquitin-proteasome pathway. Importantly, phosphorylation of PFKFB3 at Ser478 promoted glycolysis, BC cell growth, and paclitaxel resistance together with PIM2 in vitro and in vivo. CONCLUSION Our study demonstrates that PIM2 mediates PFKFB3 phosphorylation thus regulates glycolysis and paclitaxel resistance to promote tumor progression in BC and provides preclinical evidence for targeting PFKFB3 as a new strategy in BC treatment to battle paclitaxel resistance.
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Affiliation(s)
- Chao Lu
- Department of Reproductive MedicineAffiliated Hospital of Weifang Medical UniversityWeifangShandong ProvinceP. R. China
| | - Pengyun Qiao
- Department of Reproductive MedicineAffiliated Hospital of Weifang Medical UniversityWeifangShandong ProvinceP. R. China
| | - Yonghong Sun
- Department of PathologyAffiliated Hospital of Weifang Medical UniversityWeifangShandong ProvinceP. R. China
| | - Chune Ren
- Department of Reproductive MedicineAffiliated Hospital of Weifang Medical UniversityWeifangShandong ProvinceP. R. China
| | - Zhenhai Yu
- Department of Reproductive MedicineAffiliated Hospital of Weifang Medical UniversityWeifangShandong ProvinceP. R. China
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Zhang L, Liu Z, Dong Y, Kong L. E2F2 drives glioma progression via PI3K/AKT in a PFKFB4-dependent manner. Life Sci 2021; 276:119412. [PMID: 33774025 DOI: 10.1016/j.lfs.2021.119412] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/05/2021] [Accepted: 03/17/2021] [Indexed: 12/12/2022]
Abstract
AIMS The effects of PFKFB4 on glycolysis during the cancer progression has been investigated, while its role in glioma remains unclear. The present study evaluated the molecular mechanism of PFKFB4 in glycolysis of glioma progression. MATERIALS AND METHODS The pan-cancer platform SangerBox was inquired to investigate the E2F2 expression in tumors. The E2F2 expression was studied by qRT-PCR and immunohistochemistry in collected glioma and normal brain tissues and by qRT-PCR and western blot in glioma cells. The relationship between the E2F2 expression in glioma tissues and patients' prognosis was analyzed. The cell malignant phenotype, glycolysis, growth and metastasis were examined by CCK-8, EdU, colony formation, flow cytometry, wound healing, Transwell assays, ELISA kits, and tumorigenesis and metastasis assays. Downstream targets of E2F2 were searched in hTFtarget, followed by pathway enrichment analysis. The expression of these targets and their correlation with E2F2 expression in gliomas were investigated through the GEPIA website. After ChIP and luciferase assays, the effect of the target on glioma was investigated. KEY FINDINGS E2F2 was overexpressed in glioma patients and predicted poor prognoses. E2F2 promoted cell proliferation, colony formation, DNA synthesis, migration, invasion and glycolysis, and inhibited apoptosis. Meanwhile, inhibition of E2F2 suppressed the growth and metastasis of gliomas. E2F2 elevated the PFKFB4 expression transcriptionally by binding to its promoter and activated PI3K/AKT pathway. The promotion of glioma metastasis and glycolysis by E2F2 was mitigated by PFKFB4 knockdown. SIGNIFICANCE E2F2-mediated transcriptional enhancement of PFKFB4 expression regulated the phosphorylation of PI3K/AKT to promote glioma malignancy progression.
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Affiliation(s)
- Longzhou Zhang
- Department of Neurosurgery, First Hospital Affiliated to Zhengzhou University, Zhengzhou 450000, Henan, PR China.
| | - Zengjin Liu
- Department of Neurosurgery, First Hospital Affiliated to Zhengzhou University, Zhengzhou 450000, Henan, PR China
| | - Yang Dong
- Department of Neurosurgery, First Hospital Affiliated to Zhengzhou University, Zhengzhou 450000, Henan, PR China
| | - Lingchang Kong
- Department of Neurosurgery, ZhengZhou Traditional Chinese Medicine Hospital, Zhengzhou 450000, Henan, PR China
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Carbonic Anhydrase IX Promotes Human Cervical Cancer Cell Motility by Regulating PFKFB4 Expression. Cancers (Basel) 2021; 13:cancers13051174. [PMID: 33803236 PMCID: PMC7967120 DOI: 10.3390/cancers13051174] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/07/2021] [Accepted: 03/08/2021] [Indexed: 12/27/2022] Open
Abstract
Simple Summary Carbonic anhydrase IX (CAIX) is a hypoxia-induced protein that is highly expressed in numerous human cancers. However, the molecular mechanisms involved in CAIX and human cervical cancer metastasis remain poorly understood. Our study found that CAIX overexpression increases PFKFB4 expression and EMT, promoting cervical cancer cell migration. CAIX could contribute to cervical cancer cell metastasis and its inhibition could be a cervical cancer treatment strategy. Abstract Carbonic anhydrase IX (CAIX) is a hypoxia-induced protein that is highly expressed in numerous human cancers. However, the molecular mechanisms involved in CAIX and human cervical cancer metastasis remain poorly understood. In this study, CAIX overexpression in SiHa cells increased cell migration and epithelial-to-mesenchymal transition (EMT). Silencing CAIX in the Caski cell line decreased the motility of cells and EMT. Furthermore, the RNA-sequencing analysis identified a target gene, bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB4), which is influenced by CAIX overexpression and knockdown. A positive correlation was found between CAIX expression and PFKFB4 levels in the cervical cancer of the TCGA database. Mechanistically, CAIX overexpression activated the phosphorylation of extracellular signal-regulated kinases (ERKs) to induce EMT and promote cell migration. In clinical results, human cervical cancer patients with CAIXhigh/PFKFB4high expression in the late stage had higher rates of lymph node metastasis and the shortest survival time. Our study found that CAIX overexpression increases PFKFB4 expression and EMT, promoting cervical cancer cell migration. CAIX could contribute to cervical cancer cell metastasis and its inhibition could be a cervical cancer treatment strategy.
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Kotowski K, Rosik J, Machaj F, Supplitt S, Wiczew D, Jabłońska K, Wiechec E, Ghavami S, Dzięgiel P. Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets. Cancers (Basel) 2021; 13:909. [PMID: 33671514 PMCID: PMC7926708 DOI: 10.3390/cancers13040909] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/12/2021] [Accepted: 02/14/2021] [Indexed: 12/11/2022] Open
Abstract
Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.
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Affiliation(s)
- Krzysztof Kotowski
- Department of Histology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (K.K.); (K.J.)
| | - Jakub Rosik
- Department of Pathology, Pomeranian Medical University, 71-252 Szczecin, Poland; (J.R.); (F.M.)
| | - Filip Machaj
- Department of Pathology, Pomeranian Medical University, 71-252 Szczecin, Poland; (J.R.); (F.M.)
| | - Stanisław Supplitt
- Department of Genetics, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Daniel Wiczew
- Department of Biochemical Engineering, Wroclaw University of Science and Technology, 50-370 Wroclaw, Poland;
- Laboratoire de physique et chimie théoriques, Université de Lorraine, F-54000 Nancy, France
| | - Karolina Jabłońska
- Department of Histology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (K.K.); (K.J.)
| | - Emilia Wiechec
- Department of Biomedical and Clinical Sciences (BKV), Division of Cell Biology, Linköping University, Region Östergötland, 581 85 Linköping, Sweden;
- Department of Otorhinolaryngology in Linköping, Anesthetics, Operations and Specialty Surgery Center, Region Östergötland, 581 85 Linköping, Sweden
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Research Institute in Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Piotr Dzięgiel
- Department of Histology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (K.K.); (K.J.)
- Department of Physiotherapy, Wroclaw University School of Physical Education, 51-612 Wroclaw, Poland
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Wang F, Wu X, Li Y, Cao X, Zhang C, Gao Y. PFKFB4 as a promising biomarker to predict a poor prognosis in patients with gastric cancer. Oncol Lett 2021; 21:296. [PMID: 33732372 PMCID: PMC7905623 DOI: 10.3892/ol.2021.12557] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 12/14/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most common types of cancer worldwide. Previous studies have reported that phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) functions as an oncoprotein in various types of cancer. However, the association between PFKFB4 and GC remains unclear. The present study analyzed the expression levels of PFKFB4 in 148 GC tissue samples, including 46 tumor tissues with matched adjacent normal tissues, using immunohistochemistry, compared the expression levels of PFKFB4 between GC and adjacent normal tissues, and determined the association between PFKFB4 expression levels and patient clinicopathological characteristics. In addition, survival curves were generated using the Kaplan-Meier (KM) plotter database to evaluate the association between PFKFB4 expression and GC prognosis. The results revealed that PFKFB4 expression was upregulated in GC tissues compared with in adjacent normal tissues. PFKFB4 expression was associated with patient age, tumor size, pathological tumor (pT) stage and tumor-node-metastasis (pTNM) stage, and upregulated expression levels of PFKFB4 were observed in tumor tissues from patients <65 years old (compared with that in patients ≥65 years old), as well as patients with a larger tumor size and an advanced stage (pT and pTNM stage) disease. In addition, KM survival analysis demonstrated that patients with low PFKFB4 expression had a significantly improved overall survival (OS), first progression survival and post-progression survival times compared with those with high PFKFB4 expression. Furthermore, PFKFB4 expression was negatively associated with OS time in patients with late pT and pTNM stage disease. In conclusion, the results of the present study indicated that the upregulated PFKFB4 expression in GC tissues may serve as a biomarker for a more advanced disease and a poor prognosis in patients with GC.
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Affiliation(s)
- Fang Wang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Xiaoting Wu
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China.,Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Yajun Li
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Xiangmei Cao
- Department of Pathology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Cao Zhang
- Department of General Surgery, General Hospital of Ningxia Medical University, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Yujing Gao
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
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Meng J, Chen X, Han Z. PFKFB4 promotes lung adenocarcinoma progression via phosphorylating and activating transcriptional coactivator SRC-2. BMC Pulm Med 2021; 21:60. [PMID: 33593309 PMCID: PMC7887818 DOI: 10.1186/s12890-021-01420-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 01/27/2021] [Indexed: 11/22/2022] Open
Abstract
Background To investigate the role and its potential mechanism of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) in lung adenocarcinoma. Methods Co-immunoprecipitation was performed to analyze the interaction between PFKFB4 and SRC-2. Western blot was used to investigate the phosphorylation of steroid receptor coactivator-2 (SRC-2) on the condition that PFKFB4 was knockdown. Transcriptome sequencing was performed to find the downstream target of SRC-2. Cell Counting Kit-8 (CCK-8) assay, transwell assay and transwell-matrigel assay were used to examine the proliferation, migration and invasion abilities in A549 and NCI-H1975 cells with different treatment. Results In our study we found that PFKFB4 was overexpressed in lung adenocarcinoma associated with SRC family protein and had an interaction with SRC-2. PFKFB4 could phosphorylate SRC-2 at Ser487, which altered SRC-2 transcriptional activity. Functionally, PFKFB4 promoted lung adenocarcinoma cells proliferation, migration and invasion by phosphorylating SRC-2. Furthermore, we identified that CARM1 was transcriptionally regulated by SRC-2 and involved in PFKFB4-SRC-2 axis on lung adenocarcinoma progression. Conclusions Our research reveal that PFKFB4 promotes lung adenocarcinoma cells proliferation, migration and invasion via enhancing phosphorylated SRC-2-mediated CARM1 expression.
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Affiliation(s)
- Jiguang Meng
- Department of Respiratory Medicine, Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100048, China
| | - Xuxin Chen
- Department of Respiratory Medicine, Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100048, China
| | - Zhihai Han
- Department of Respiratory Medicine, Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100048, China.
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Gu X, Guan J, Xu J, Zheng Q, Chen C, Yang Q, Huang C, Wang G, Zhou H, Chen Z, Zhu H. Model based on five tumour immune microenvironment-related genes for predicting hepatocellular carcinoma immunotherapy outcomes. J Transl Med 2021; 19:26. [PMID: 33407546 PMCID: PMC7788940 DOI: 10.1186/s12967-020-02691-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 12/22/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Although the tumour immune microenvironment is known to significantly influence immunotherapy outcomes, its association with changes in gene expression patterns in hepatocellular carcinoma (HCC) during immunotherapy and its effect on prognosis have not been clarified. METHODS A total of 365 HCC samples from The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset were stratified into training datasets and verification datasets. In the training datasets, immune-related genes were analysed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO)-Cox analyses to build a prognostic model. The TCGA-LIHC, GSE14520, and Imvigor210 cohorts were subjected to time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival curve analyses to verify the reliability of the developed model. Finally, single-sample gene set enrichment analysis (ssGSEA) was used to study the underlying molecular mechanisms. RESULTS Five immune-related genes (LDHA, PPAT, BFSP1, NR0B1, and PFKFB4) were identified and used to establish the prognostic model for patient response to HCC treatment. ROC curve analysis of the TCGA (training and validation sets) and GSE14520 cohorts confirmed the predictive ability of the five-gene-based model (AUC > 0.6). In addition, ROC and Kaplan-Meier analyses indicated that the model could stratify patients into a low-risk and a high-risk group, wherein the high-risk group exhibited worse prognosis and was less sensitive to immunotherapy than the low-risk group. Functional enrichment analysis predicted potential associations of the five genes with several metabolic processes and oncological signatures. CONCLUSIONS We established a novel five-gene-based prognostic model based on the tumour immune microenvironment that can predict immunotherapy efficacy in HCC patients.
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Affiliation(s)
- Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Jia Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Qiuxian Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Chao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Qin Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Chunhong Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Gang Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Haibo Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, NO. 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
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Cao L, Wu J, Qu X, Sheng J, Cui M, Liu S, Huang X, Xiang Y, Li B, Zhang X, Cui R. Glycometabolic rearrangements--aerobic glycolysis in pancreatic cancer: causes, characteristics and clinical applications. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:267. [PMID: 33256814 PMCID: PMC7708116 DOI: 10.1186/s13046-020-01765-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 11/05/2020] [Indexed: 12/11/2022]
Abstract
Pancreatic cancer is one of the most malignant tumors worldwide, and pancreatic ductal adenocarcinoma is the most common type. In pancreatic cancer, glycolysis is the primary way energy is produced to maintain the proliferation, invasion, migration, and metastasis of cancer cells, even under normoxia. However, the potential molecular mechanism is still unknown. From this perspective, this review mainly aimed to summarize the current reasonable interpretation of aerobic glycolysis in pancreatic cancer and some of the newest methods for the detection and treatment of pancreatic cancer. More specifically, we reported some biochemical parameters, such as newly developed enzymes and transporters, and further explored their potential as diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Lidong Cao
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, 130041, China.,Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, Changchun, 130041, China
| | - Jiacheng Wu
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, 130041, China.,Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, Changchun, 130041, China
| | - Xianzhi Qu
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, 130041, China.,Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, Changchun, 130041, China
| | - Jiyao Sheng
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, 130041, China.,Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, Changchun, 130041, China
| | - Mengying Cui
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, 130041, China.,Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, Changchun, 130041, China
| | - Shui Liu
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, 130041, China.,Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, Changchun, 130041, China
| | - Xu Huang
- Department of Hepatobiliary and Pancreatic Surgery, the First Bethune Hospital of Jilin University, Changchun, 130021, China
| | - Yien Xiang
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, 130041, China.,Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, Changchun, 130041, China
| | - Bingjin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, China
| | - Xuewen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, 130041, China. .,Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, Changchun, 130041, China.
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, China.
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Farhadi P, Yarani R, Dokaneheifard S, Mansouri K. The emerging role of targeting cancer metabolism for cancer therapy. Tumour Biol 2020; 42:1010428320965284. [PMID: 33028168 DOI: 10.1177/1010428320965284] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Glucose, as the main consuming nutrient of the body, faces different destinies in cancer cells. Glycolysis, oxidative phosphorylation, and pentose phosphate pathways produce different glucose-derived metabolites and thus affect cells' bioenergetics differently. Tumor cells' dependency to aerobic glycolysis and other cancer-specific metabolism changes are known as the cancer hallmarks, distinct cancer cells from normal cells. Therefore, these tumor-specific characteristics receive the limelight as targets for cancer therapy. Glutamine, serine, and fatty acid oxidation together with 5-lipoxygenase are main pathways that have attracted lots of attention for cancer therapy. In this review, we not only discuss different tumor metabolism aspects but also discuss the metabolism roles in the promotion of cancer cells at different stages and their difference with normal cells. Besides, we dissect the inhibitors potential in blocking the main metabolic pathways to introduce the effective and non-effective inhibitors in the field.
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Affiliation(s)
- Pegah Farhadi
- Medical Biology Research Center, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Sadat Dokaneheifard
- Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kamran Mansouri
- Medical Biology Research Center, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Molecular Medicine, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Deng X, Li D, Ke X, Wang Q, Yan S, Xue Y, Wang Q, Zheng H. Mir-488 alleviates chemoresistance and glycolysis of colorectal cancer by targeting PFKFB3. J Clin Lab Anal 2020. [PMID: 32990355 DOI: 10.1002/jcla.23578.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Considering the boosting effect of glycolysis on tumor chemoresistance, this investigation aimed at exploring whether miR-488/PFKFB3 axis might reduce drug resistance of colorectal cancer (CRC) by affecting glycolysis, proliferation, migration, and invasion of CRC cells. METHOD Totally, 288 CRC patients were divided into metastasis/recurrence group (n = 107) and non-metastasis/recurrence group (n = 181) according to their prognosis about 1 year after the chemotherapy, and their 3-year overall survival was also tracked. Besides, miR-488 expression was determined in peripheral blood of CRC patients and also in CRC cell lines (ie, W620, HT-29, Lovo, and HCT116). The targeted relationship between miR-488 and PFKFB3 was predicted by Targetscan software and confirmed by dual-luciferase reporter gene assay. Moreover, glycolysis and drug tolerance of CRC cells lines were assessed. RESULTS MiR-488 expression was significantly decreased in metastatic/recurrent CRC patients than those without metastasis/recurrence (P < .05), and lowly expressed miR-488 was suggestive of unfavorable 3-year survival, large tumor size, poor differentiation, in-depth infiltration, and advanced Duke stage of CRC patients (P < .05). Besides, CRC cell lines transfected by miR-488 mimic demonstrated decreases in glucose uptake and lactate secretion, increases in oxaliplatin/5-Fu-sensistivity, as well as diminished capability of proliferating, invading, and migratory (P < .05), which were reversible by extra transfection of pcDNA3.1-PFKFB3 (ie, miR-488 mimic + pcDNA3.1-PFKFB3 group). Finally, the mRNA level of PFKFB3 was down-regulated by miR-488 mimic in CRC cell lines after being targeted by it (P < .05). CONCLUSION The miR-488/PFKFB3 axis might clinically refine chemotherapeutic efficacy of CRC, given its modifying glycolysis and metastasis of CRC cells.
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Affiliation(s)
- Xiaojing Deng
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Dapeng Li
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Xiquan Ke
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Qizhi Wang
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Shanjun Yan
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Yongju Xue
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Qiangwu Wang
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Hailun Zheng
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
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Deng X, Li D, Ke X, Wang Q, Yan S, Xue Y, Wang Q, Zheng H. Mir-488 alleviates chemoresistance and glycolysis of colorectal cancer by targeting PFKFB3. J Clin Lab Anal 2020; 35:e23578. [PMID: 32990355 PMCID: PMC7843269 DOI: 10.1002/jcla.23578] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 07/03/2020] [Accepted: 07/23/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Considering the boosting effect of glycolysis on tumor chemoresistance, this investigation aimed at exploring whether miR-488/PFKFB3 axis might reduce drug resistance of colorectal cancer (CRC) by affecting glycolysis, proliferation, migration, and invasion of CRC cells. METHOD Totally, 288 CRC patients were divided into metastasis/recurrence group (n = 107) and non-metastasis/recurrence group (n = 181) according to their prognosis about 1 year after the chemotherapy, and their 3-year overall survival was also tracked. Besides, miR-488 expression was determined in peripheral blood of CRC patients and also in CRC cell lines (ie, W620, HT-29, Lovo, and HCT116). The targeted relationship between miR-488 and PFKFB3 was predicted by Targetscan software and confirmed by dual-luciferase reporter gene assay. Moreover, glycolysis and drug tolerance of CRC cells lines were assessed. RESULTS MiR-488 expression was significantly decreased in metastatic/recurrent CRC patients than those without metastasis/recurrence (P < .05), and lowly expressed miR-488 was suggestive of unfavorable 3-year survival, large tumor size, poor differentiation, in-depth infiltration, and advanced Duke stage of CRC patients (P < .05). Besides, CRC cell lines transfected by miR-488 mimic demonstrated decreases in glucose uptake and lactate secretion, increases in oxaliplatin/5-Fu-sensistivity, as well as diminished capability of proliferating, invading, and migratory (P < .05), which were reversible by extra transfection of pcDNA3.1-PFKFB3 (ie, miR-488 mimic + pcDNA3.1-PFKFB3 group). Finally, the mRNA level of PFKFB3 was down-regulated by miR-488 mimic in CRC cell lines after being targeted by it (P < .05). CONCLUSION The miR-488/PFKFB3 axis might clinically refine chemotherapeutic efficacy of CRC, given its modifying glycolysis and metastasis of CRC cells.
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Affiliation(s)
- Xiaojing Deng
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Dapeng Li
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Xiquan Ke
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Qizhi Wang
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Shanjun Yan
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Yongju Xue
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Qiangwu Wang
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
| | - Hailun Zheng
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China
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Feng J, Li J, Wu L, Yu Q, Ji J, Wu J, Dai W, Guo C. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:126. [PMID: 32631382 PMCID: PMC7336654 DOI: 10.1186/s13046-020-01629-4] [Citation(s) in RCA: 381] [Impact Index Per Article: 76.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 06/25/2020] [Indexed: 12/14/2022]
Abstract
Liver cancer has become the sixth most diagnosed cancer and the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is responsible for up to 75–85% of primary liver cancers, and sorafenib is the first targeted drug for advanced HCC treatment. However, sorafenib resistance is common because of the resultant enhancement of aerobic glycolysis and other molecular mechanisms. Aerobic glycolysis was firstly found in HCC, acts as a hallmark of liver cancer and is responsible for the regulation of proliferation, immune evasion, invasion, metastasis, angiogenesis, and drug resistance in HCC. The three rate-limiting enzymes in the glycolytic pathway, including hexokinase 2 (HK2), phosphofructokinase 1 (PFK1), and pyruvate kinases type M2 (PKM2) play an important role in the regulation of aerobic glycolysis in HCC and can be regulated by many mechanisms, such as the AMPK, PI3K/Akt pathway, HIF-1α, c-Myc and noncoding RNAs. Because of the importance of aerobic glycolysis in the progression of HCC, targeting key factors in its pathway such as the inhibition of HK2, PFK or PKM2, represent potential new therapeutic approaches for the treatment of HCC.
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Affiliation(s)
- Jiao Feng
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China.,Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Jingjing Li
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China.,Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Qiang Yu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Jie Ji
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China.
| | - Weiqi Dai
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China. .,Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China. .,Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China. .,Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, 200032, China. .,Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200336, China.
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People's Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China. .,Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, number 301, Middle Yanchang road, Jing'an, Shanghai, 200072, China.
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Zhao Q, Li J, Wu B, Shang Y, Huang X, Dong H, Liu H, Chen W, Gui R, Nie X. Smart Biomimetic Nanocomposites Mediate Mitochondrial Outcome through Aerobic Glycolysis Reprogramming: A Promising Treatment for Lymphoma. ACS APPLIED MATERIALS & INTERFACES 2020; 12:22687-22701. [PMID: 32330381 DOI: 10.1021/acsami.0c05763] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Toxicity and drug resistance caused by chemotherapeutic drugs have become bottlenecks in treating tumors. The delivery of anticancer drugs based on nanocarriers is regarded as an ideal way to solve the aforementioned problems. In this study, a new antilymphoma nanodrug CD20 aptamer-RBCm@Ag-MOFs/PFK15 (A-RAMP) is designed and constructed, and it consists of two parts: (1) metal-organic frameworks Ag-MOFs (AM) loaded with tumor aerobic glycolysis inhibitor PFK15 (P), forming a core part (AMP); (2) targeted molecule CD20 aptamer (A) is inserted into the red blood cell membrane (RBCm) to form the shell part (A-R). A-RAMP under the guidance of CD20 aptamer actively targets B-cell lymphoma both in vitro and in vivo. As a result, A-RAMP not only significantly inhibits the effect on tumor growth but also shows no obvious side effects on the treated nude mice, indicating that A-RAMP can accurately target tumor cells, reprogram aerobic glycolysis, and exert synergistic antitumor effect by Ag+ and PFK 15. Furthermore, the antitumor mechanism of A-RAMP in vivo by apoptotic pathway and targeting metabonomics are explored. These results suggest that A-RAMP has a promising application prospect as an smart, safe, effective, and synergistic antilymphoma agent.
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Affiliation(s)
- Qiangqiang Zhao
- Department of Blood Transfusion, the Third Xiangya Hospital, Central South University, Changsha 410013, P. R. China
- Department of Hematology, The Qinghai Provincial People's Hospital, Xining 810007, P. R. China
| | - Jian Li
- Department of Blood Transfusion, the Third Xiangya Hospital, Central South University, Changsha 410013, P. R. China
| | - Bin Wu
- Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P. R. China
| | - Yinghui Shang
- Department of Blood Transfusion, the Third Xiangya Hospital, Central South University, Changsha 410013, P. R. China
| | - Xueyuan Huang
- Department of Blood Transfusion, the Third Xiangya Hospital, Central South University, Changsha 410013, P. R. China
| | - Hang Dong
- Department of Blood Transfusion, the Third Xiangya Hospital, Central South University, Changsha 410013, P. R. China
| | - Haiting Liu
- Department of Blood Transfusion, the Third Xiangya Hospital, Central South University, Changsha 410013, P. R. China
| | - Wansong Chen
- College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P. R. China
| | - Rong Gui
- Department of Blood Transfusion, the Third Xiangya Hospital, Central South University, Changsha 410013, P. R. China
| | - Xinmin Nie
- Clinical Laboratory of the Third Xiangya Hospital, Central South University, Changsha 410013, P. R. China
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PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells. Mol Cell Biochem 2020; 470:115-129. [PMID: 32415418 DOI: 10.1007/s11010-020-03751-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 05/08/2020] [Indexed: 12/27/2022]
Abstract
Tumor cells increase glucose metabolism through glycolysis and pentose phosphate pathways to meet the bioenergetic and biosynthetic demands of rapid cell proliferation. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are key regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent activator of glycolysis. Previous studies have reported the co-expression of PFKFB isozymes, as well as the mRNA splice variants of particular PFKFB isozymes, suggesting non-redundant functions. Majority of the evidence demonstrating a requirement for PFKFB activity in increased glycolysis and oncogenic properties in tumor cells comes from studies on PFKFB3 and PFKFB4 isozymes. In this study, we show that the PFKFB2 isozyme is expressed in tumor cell lines of various origin, overexpressed and localizes to the nucleus in pancreatic adenocarcinoma, relative to normal pancreatic tissue. We then demonstrate the differential intracellular localization of two PFKFB2 mRNA splice variants and that, when ectopically expressed, cytoplasmically localized mRNA splice variant causes a greater increase in F2,6BP which coincides with an increased glucose uptake, as compared with the mRNA splice variant localizing to the nucleus. We then show that PFKFB2 expression is required for steady-state F2,6BP levels, glycolytic activity, and proliferation of pancreatic adenocarcinoma cells. In conclusion, this study may provide a rationale for detailed investigation of PFKFB2's requirement for the glycolytic and oncogenic phenotype of pancreatic adenocarcinoma cells.
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46
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Isorhamnetin Induces Melanoma Cell Apoptosis via the PI3K/Akt and NF- κB Pathways. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1057943. [PMID: 32461960 PMCID: PMC7225865 DOI: 10.1155/2020/1057943] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 03/31/2020] [Indexed: 01/04/2023]
Abstract
Malignant melanoma is characterized by its bad prognosis for aggressiveness, drug resistance, and early metastasis. Isorhamnetin (3′-methoxy-3,4′,5,7-tetrahydroxyflavone; IH) is a natural flavonoid that has been investigated for its antitumor effects in breast cancer, colon cancer, and gastric cancer through inducing cell apoptosis. Given its role in tumor inhibition, no research has been conducted concerning its effect against melanoma. In the present study, we found that IH could significantly inhibit B16F10 cell proliferation and migration and induce B16F10 cell apoptosis. The examination on molecular mechanism revealed that IH could suppress the phosphorylation of Akt and the translocation of NF-κB, which are key factors in apoptosis-related pathways. We also detected that this process was related to the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases 4 (PFKFB4) by PFKFB4 knockdown experiment. In line with in vitro study, we further provided that IH effectively inhibited tumor growth in vivo. Taken together, IH was proven to induce melanoma cell apoptosis in vitro and in vivo, which may serve as a potential agent in malignant melanoma treatment in the future.
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Lei Y, Chen T, Li Y, Shang M, Zhang Y, Jin Y, Yu Q, Guo F, Wang T. O-GlcNAcylation of PFKFB3 is required for tumor cell proliferation under hypoxia. Oncogenesis 2020; 9:21. [PMID: 32060258 PMCID: PMC7021673 DOI: 10.1038/s41389-020-0208-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 02/05/2020] [Accepted: 02/05/2020] [Indexed: 12/27/2022] Open
Abstract
The protein O-GlcNAcylation catalysed by O-GlcNAc transferase (OGT) is tightly regulated by glucose availability. It is upregulated and essential for tumor cell proliferation under hypoxic conditions. However, the mechanism behind is still unclear. Here, we showed that the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), which also promotes cell cycle progression in the nucleus, was O-GlcNAcylated in response to hypoxia. The O-GlcNAcylation of PFKFB3 could compete phosphorylation by hypoxia-activated ERK at the same modification site Ser172. Phosphorylated PFKFB3 could interact with the protein G3BP2 and retain in the cytosol; this in turn led to the accumulation of hypoxia-induced-P27 in the nucleus resulting in the cell cycle arrest. Such a pathway was compromised by high level of PFKFB3 O-GlcNAcylation in tumor cells contributing to cell cycle progression. Consistently, the PFKFB3-Ser172 phosphorylation level inversely correlated with the OGT level in pancreatic cancer patients. Our findings uncovered an O-GlcNAcylation mediated mechanism to promote tumor cell proliferation under metabolic stress, linking the aberrant OGT activity to tumorigenesis in pancreatic cancer.
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Affiliation(s)
- Yinrui Lei
- Department of Pharmacology And Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.,Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Tao Chen
- Endoscopy Center, Shanghai East Hospital, Tongji University, 150Jimo Road, Shanghai, 200120, China
| | - Yeyi Li
- Department of Pharmacology And Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Man Shang
- Department of Pharmacology And Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Yan Zhang
- Department of Pharmacology And Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Yuepeng Jin
- Department of General Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Qiujing Yu
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Fang Guo
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Ting Wang
- Department of Pharmacology And Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China. .,The Institute of Cell Metabolism and Disease, Shanghai Key Laboratory of Pancreatic Cancer, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201620, China.
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Yang J, Ren B, Yang G, Wang H, Chen G, You L, Zhang T, Zhao Y. The enhancement of glycolysis regulates pancreatic cancer metastasis. Cell Mol Life Sci 2020; 77:305-321. [PMID: 31432232 PMCID: PMC11104916 DOI: 10.1007/s00018-019-03278-z] [Citation(s) in RCA: 227] [Impact Index Per Article: 45.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 08/10/2019] [Accepted: 08/12/2019] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma is prone to distant metastasis and is expected to become the second leading cause of cancer-related death. In an extremely nutrient-deficient and hypoxic environment resulting from uncontrolled growth, vascular disturbances and desmoplastic reactions, pancreatic cancer cells utilize "metabolic reprogramming" to satisfy their energy demand and support malignant behaviors such as metastasis. Notably, pancreatic cancer cells show extensive enhancement of glycolysis, including glycolytic enzyme overexpression and increased lactate production, and this is caused by mitochondrial dysfunction, cancer driver genes, specific transcription factors, a hypoxic tumor microenvironment and stromal cells, such as cancer-associated fibroblasts and tumor-associated macrophages. The metabolic switch from oxidative phosphorylation to glycolysis in pancreatic cancer cells regulates the invasion-metastasis cascade by promoting epithelial-mesenchymal transition, tumor angiogenesis and the metastatic colonization of distant organs. In addition to aerobic glycolysis, oxidative phosphorylation also plays a critical role in pancreatic cancer metastasis in ways that remain unclear. In this review, we expound on the intracellular and extracellular causes of the enhancement of glycolysis in pancreatic cancer and the strong association between glycolysis and cancer metastasis, which we expect will yield new therapeutic approaches targeting cancer metabolism.
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Affiliation(s)
- Jinshou Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Bo Ren
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Huanyu Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Guangyu Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China.
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, People's Republic of China.
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Malila Y, Thanatsang K, Arayamethakorn S, Uengwetwanit T, Srimarut Y, Petracci M, Strasburg GM, Rungrassamee W, Visessanguan W. Absolute expressions of hypoxia-inducible factor-1 alpha (HIF1A) transcript and the associated genes in chicken skeletal muscle with white striping and wooden breast myopathies. PLoS One 2019; 14:e0220904. [PMID: 31393948 PMCID: PMC6687142 DOI: 10.1371/journal.pone.0220904] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 07/25/2019] [Indexed: 01/29/2023] Open
Abstract
Development of white striping (WS) and wooden breast (WB) in broiler breast meat have been linked to hypoxia, but their etiologies are not fully understood. This study aimed at investigating absolute expression of hypoxia-inducible factor-1 alpha subunit (HIF1A) and genes involved in stress responses and muscle repair using a droplet digital polymerase chain reaction. Total RNA was isolated from pectoralis major collected from male 6-week-old medium (carcass weight ≤ 2.5 kg) and heavy (carcass weight > 2.5 kg) broilers. Samples were classified as “non-defective” (n = 4), “medium-WS” (n = 6), “heavy-WS” (n = 7) and “heavy-WS+WB” (n = 3) based on abnormality scores. The HIF1A transcript was up-regulated in all of the abnormal groups. Transcript abundances of genes encoding 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), lactate dehydrogenase-A (LDHA), and phosphorylase kinase beta subunit (PHKB) were increased in heavy-WS but decreased in heavy-WS+WB. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was up-regulated in non-defective samples. The muscle-specific mu-2 isoform of glutathione S-transferases (GSTM2) was up-regulated in the abnormal samples, particularly in the heavy groups. The genes encoding myogenic differentiation (MYOD1) and myosin light chain kinase (MYLK) exhibited similar expression pattern, of which medium-WS and heavy-WS significantly increased compared to non-defective whereas expression in heavy-WS+WB was not different from either non-defective or WS-affected group. The greatest and the lowest levels of calpain-3 (CAPN3) and delta-sarcoglycan (SCGD) were observed in heavy-WS and heavy-WS+WB, respectively. Based on micrographs, the abnormal muscles primarily comprised fibers with cross-sectional areas ranging from 2,000 to 3,000 μm2. Despite induced glycolysis at the transcriptional level, lower stored glycogen in the abnormal muscles corresponded with the reduced lactate and higher pH within their meats. The findings support hypoxia within the abnormal breasts, potentially associated with oversized muscle fibers. Between WS and WB, divergent glucose metabolism, cellular detoxification and myoregeneration at the transcriptional level could be anticipated.
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Affiliation(s)
- Yuwares Malila
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Khlong Nueng, Khlong Luang, Pathum Thani, Thailand
- * E-mail:
| | - Krittaporn Thanatsang
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Khlong Nueng, Khlong Luang, Pathum Thani, Thailand
| | - Sopacha Arayamethakorn
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Khlong Nueng, Khlong Luang, Pathum Thani, Thailand
| | - Tanaporn Uengwetwanit
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Khlong Nueng, Khlong Luang, Pathum Thani, Thailand
| | - Yanee Srimarut
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Khlong Nueng, Khlong Luang, Pathum Thani, Thailand
| | - Massimiliano Petracci
- Department of Agricultural and Food Sciences, Alma Mater Studiorum, University of Bologna, Cesena (FC), Italy
| | - Gale M. Strasburg
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, United States of America
| | - Wanilada Rungrassamee
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Khlong Nueng, Khlong Luang, Pathum Thani, Thailand
| | - Wonnop Visessanguan
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Khlong Nueng, Khlong Luang, Pathum Thani, Thailand
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Kessler R, Fleischer M, Springsguth C, Bigl M, Warnke JP, Eschrich K. Prognostic Value of PFKFB3 to PFKFB4 mRNA Ratio in Patients With Primary Glioblastoma (IDH-Wildtype). J Neuropathol Exp Neurol 2019; 78:865-870. [DOI: 10.1093/jnen/nlz067] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 11/23/2018] [Accepted: 07/02/2019] [Indexed: 12/25/2022] Open
Abstract
Abstract
A hallmark of glioblastoma is the high level of aerobic glycolysis. PFKFB3 and PFKFB4 are regulatory glycolytic enzymes, which are overexpressed in glioblastomas. Selective inhibition of these enzymes has emerged as a new approach in tumor therapy. We investigated the ratios of PFKFB3 to PFKFB4 mRNA expression in 66 astrocytic tumors of different malignancy grades. PFKFB3 mRNA levels were considerably higher than those of PFKFB4 in all analyzed tumors. IDH-wildtype glioblastomas showed lower PFKFB3 to PFKFB4 mRNA ratios (7.7:1) than IDH-mutant low-grade astrocytomas (36.5:1), indicating a dependency of the ratio on malignancy grade. In IDH-wildtype glioblastomas exhibiting loss of heterozygosity (LOH) of the PFKFB3 gene locus, the decrease of PFKFB3 mRNA levels was accompanied by lower PFKFB4 mRNA levels, but the PFKFB3 to PFKFB4 mRNA ratio did not differ between tumors with or without PFKFB3 LOH. IDH-wildtype primary glioblastoma patients with high PFKFB3 to PFKFB4 mRNA ratios above the average of 7.7:1 had a significantly longer overall survival time (14 months) than patients with lower ratios (9 months). Our results indicate that low PFKFB3 to PFKFB4 expression ratio is a poor prognostic factor in patients with IDH-wildtype primary glioblastoma and that PFKFB3 and PFKFB4 might represent promising targets for astrocytoma and glioblastoma treatment.
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Affiliation(s)
- Renate Kessler
- Rudolf Schoenheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, University of Leipzig, Germany
| | | | - Christopher Springsguth
- Rudolf Schoenheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, University of Leipzig, Germany
| | - Marina Bigl
- Rudolf Schoenheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, University of Leipzig, Germany
| | - Jan-Peter Warnke
- Department of Neurosurgery, Paracelsus Hospital, Zwickau, Germany
| | - Klaus Eschrich
- Rudolf Schoenheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, University of Leipzig, Germany
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