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Li B, Che Y, Zhu P, Xu Y, Yu H, Li D, Ding X. A novel basement membrane-related gene signature predicts prognosis and immunotherapy response in hepatocellular carcinoma. Front Oncol 2024; 14:1388016. [PMID: 39070142 PMCID: PMC11272612 DOI: 10.3389/fonc.2024.1388016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 06/28/2024] [Indexed: 07/30/2024] Open
Abstract
Background Basement membranes (BMs) have recently emerged as significant players in cancer progression and metastasis, rendering them promising targets for potential anti-cancer therapies. Here, we aimed to develop a novel signature of basement membrane-related genes (BMRGs) for the prediction of clinical prognosis and tumor microenvironment in hepatocellular carcinoma (HCC). Methods The differentially expressed BMRGs were subjected to univariate Cox regression analysis to identify BMRGs with prognostic significance. A six-BMRGs risk score model was constructed using Least Absolute Shrinkage Selection Operator (LASSO) Cox regression. Furthermore, a nomogram incorporating the BMRGs score and other clinicopathological features was developed for accurate prediction of survival rate in patients with HCC. Results A total of 121 differentially expressed BMRGs were screened from the TCGA HCC cohort. The functions of these BMRGs were significantly enriched in the extracellular matrix structure and signal transduction. The six-BMRGs risk score, comprising CD151, CTSA, MMP1, ROBO3, ADAMTS5 and MEP1A, was established for the prediction of clinical prognosis, tumor microenvironment characteristics, and immunotherapy response in HCC. Kaplan-Meier analysis revealed that the BMRGs score-high group showed a significantly shorter overall survival than BMRGs score-low group. A nomogram showed that the BMRGs score could be used as a new effective clinical predictor and can be combined with other clinical variables to improve the prognosis of patients with HCC. Furthermore, the high BMRGs score subgroup exhibited an immunosuppressive state characterized by infiltration of macrophages and T-regulatory cells, elevated tumor immune dysfunction and exclusion (TIDE) score, as well as enhanced expression of immune checkpoints including PD-1, PD-L1, CTLA4, PD-L2, HAVCR2, and TIGIT. Finally, a multi-step analysis was conducted to identify two pivotal hub genes, PKM and ITGA3, in the high-scoring group of BMRGs, which exhibited significant associations with an unfavorable prognosis in HCC. Conclusion Our study suggests that the BMRGs score can serve as a robust biomarker for predicting clinical outcomes and evaluating the tumor microenvironment in patients with HCC, thereby facilitating more effective clinical implementation of immunotherapy.
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Affiliation(s)
- Bingyao Li
- Henan Provincial People’s Hospital, Xinxiang Medical University, Xinxiang, Henan, China
- Henan Provincial Key Medical Laboratory for Hepatobiliary and Pancreatic Diseases, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
| | - Yingkun Che
- Henan Provincial Key Medical Laboratory for Hepatobiliary and Pancreatic Diseases, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
| | - Puhua Zhu
- Henan Provincial Key Medical Laboratory for Hepatobiliary and Pancreatic Diseases, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
- Department of Hepatobiliary Pancreatic Surgery, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
| | - Yuanpeng Xu
- Henan Provincial Key Medical Laboratory for Hepatobiliary and Pancreatic Diseases, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
| | - Haibo Yu
- Henan Provincial People’s Hospital, Xinxiang Medical University, Xinxiang, Henan, China
- Department of Hepatobiliary Pancreatic Surgery, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
| | - Deyu Li
- Henan Provincial People’s Hospital, Xinxiang Medical University, Xinxiang, Henan, China
- Henan Provincial Key Medical Laboratory for Hepatobiliary and Pancreatic Diseases, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
- Department of Hepatobiliary Pancreatic Surgery, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
| | - Xiangming Ding
- Henan Provincial People’s Hospital, Xinxiang Medical University, Xinxiang, Henan, China
- Department of Gastroenterology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
- Henan Key Medical Laboratory for Molecular Immunology of Digestive Diseases, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
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Inoue M, Nakagawa Y, Azuma M, Akahane H, Chimori R, Mano Y, Takasawa R. The PKM2 inhibitor shikonin enhances piceatannol-induced apoptosis of glyoxalase I-dependent cancer cells. Genes Cells 2024; 29:52-62. [PMID: 37963646 PMCID: PMC11448369 DOI: 10.1111/gtc.13084] [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: 06/20/2023] [Revised: 11/06/2023] [Accepted: 11/06/2023] [Indexed: 11/16/2023]
Abstract
Glyoxalase I (GLO I), a major enzyme involved in the detoxification of the anaerobic glycolytic byproduct methylglyoxal, is highly expressed in various tumors, and is regarded as a promising target for cancer therapy. We recently reported that piceatannol potently inhibits human GLO I and induces the death of GLO I-dependent cancer cells. Pyruvate kinase M2 (PKM2) is also a potential therapeutic target for cancer treatment, so we evaluated the combined anticancer efficacy of piceatannol plus low-dose shikonin, a potent and specific plant-derived PKM2 inhibitor, in two GLO I-dependent cancer cell lines, HL-60 human myeloid leukemia cells and NCI-H522 human non-small-cell lung cancer cells. Combined treatment with piceatannol and low-dose shikonin for 48 h synergistically reduced cell viability, enhanced apoptosis rate, and increased extracellular methylglyoxal accumulation compared to single-agent treatment, but did not alter PKM1, PKM2, or GLO I protein expression. Taken together, these results indicate that concomitant use of low-dose shikonin potentiates piceatannol-induced apoptosis of GLO I-dependent cancer cells by augmenting methylglyoxal accumulation.
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Affiliation(s)
- Manami Inoue
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Yuki Nakagawa
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Miku Azuma
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Haruka Akahane
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Ryusei Chimori
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Yasunari Mano
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Ryoko Takasawa
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
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Xu H, Li L, Dong B, Lu J, Zhou K, Yin X, Sun H. TRAF6 promotes chemoresistance to paclitaxel of triple negative breast cancer via regulating PKM2-mediated glycolysis. Cancer Med 2023; 12:19807-19820. [PMID: 37746908 PMCID: PMC10587986 DOI: 10.1002/cam4.6552] [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: 04/07/2023] [Revised: 08/22/2023] [Accepted: 09/08/2023] [Indexed: 09/26/2023] Open
Abstract
Ample evidence reveals that glycolysis is crucial to tumor progression; however, the underlying mechanism of its drug resistance is still worth being further explored. TRAF6, an E3 ubiquitin ligase, is well recognized to overexpress in various types of cancer, which predicts a poor prognosis. In our study, we discovered that TRAF6 was expressed more significantly in the case of triple-negative breast cancer (TNBC) than in other of breast cancers, promoting chemoresistance to paclitaxel; that inhibited TRAF6 expression in the chemoresistant TNBC (TNBC-CR) cells enhanced the sensitivity by decreasing glucose uptake and lactate production; that TRAF6 regulated glycolysis and facilitated chemoresistance via binding directly to PKM2; and that overexpressing PKM2 in the TNBC-CR cells with TRAF6 knocked down regained significantly TRAF6-dependent drug resistance and glycolysis. Additionally, we verified that TRAF6 could facilitate PKM2-mediated glycolysis and chemoresistance in animal models and clinical tumor tissues. Thus, we identified the novel function of TRAF6 to promote glycolysis and drug resistance in TNBC with the regulation of PKM2, which could provide a potential molecular target for TNBC treatment.
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Affiliation(s)
- Han Xu
- Department of General SurgeryJing'an District Center Hospital of ShanghaiShanghaiChina
| | - Longzhi Li
- Department of General SurgeryJing'an District Center Hospital of ShanghaiShanghaiChina
| | - Bing Dong
- Department of General SurgeryJing'an District Center Hospital of ShanghaiShanghaiChina
| | - Ji Lu
- Department of General SurgeryJing'an District Center Hospital of ShanghaiShanghaiChina
| | - Kun Zhou
- Department of General SurgeryJing'an District Center Hospital of ShanghaiShanghaiChina
| | - Xiaoxing Yin
- Department of General SurgeryJing'an District Center Hospital of ShanghaiShanghaiChina
| | - Huizhen Sun
- Department of Obstetrics and GynecologyXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
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Li Y, Huang H, Wu S, Zhou Y, Huang T, Jiang J. The Role of RNA m 6A Modification in Cancer Glycolytic Reprogramming. Curr Gene Ther 2023; 23:51-59. [PMID: 36043793 DOI: 10.2174/1566523222666220830150446] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 07/19/2022] [Accepted: 07/28/2022] [Indexed: 02/08/2023]
Abstract
As one of the main characteristics of neoplasia, metabolic reprogramming provides nutrition and energy to enhance cell proliferation and maintain environment homeostasis. Glycolysis is one of the most important components of cancer metabolism and the Warburg effect contributes to the competitive advantages of cancer cells in the threatened microenvironment. Studies show strong links between N6-methyladenosine (m6A) modification and metabolic recombination of cancer cells. As the most abundant modification in eukaryotic RNA, m6A methylation plays important roles in regulating RNA processing, including splicing, stability, transportation, translation and degradation. The aberration of m6A modification can be observed in a variety of diseases such as diabetes, neurological diseases and cancers. This review describes the mechanisms of m6A on cancer glycolysis and their applications in cancer therapy and prognosis evaluation, aiming to emphasize the importance of targeting m6A in modulating cancer metabolism.
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Affiliation(s)
- Yuanqi Li
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China
- Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Hao Huang
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China
- Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Shaoxian Wu
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China
- Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - You Zhou
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China
- Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Tao Huang
- Bio-Med Big Data Center, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jingting Jiang
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China
- Institute of Cell Therapy, Soochow University, Changzhou 213003, China
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Feng Z, Ou Y, Hao L. The roles of glycolysis in osteosarcoma. Front Pharmacol 2022; 13:950886. [PMID: 36059961 PMCID: PMC9428632 DOI: 10.3389/fphar.2022.950886] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/25/2022] [Indexed: 12/02/2022] Open
Abstract
Metabolic reprogramming is of great significance in the progression of various cancers and is critical for cancer progression, diagnosis, and treatment. Cellular metabolic pathways mainly include glycolysis, fat metabolism, glutamine decomposition, and oxidative phosphorylation. In cancer cells, reprogramming metabolic pathways is used to meet the massive energy requirement for tumorigenesis and development. Metabolisms are also altered in malignant osteosarcoma (OS) cells. Among reprogrammed metabolisms, alterations in aerobic glycolysis are key to the massive biosynthesis and energy demands of OS cells to sustain their growth and metastasis. Numerous studies have demonstrated that compared to normal cells, glycolysis in OS cells under aerobic conditions is substantially enhanced to promote malignant behaviors such as proliferation, invasion, metastasis, and drug resistance of OS. Glycolysis in OS is closely related to various oncogenes and tumor suppressor genes, and numerous signaling pathways have been reported to be involved in the regulation of glycolysis. In recent years, a vast number of inhibitors and natural products have been discovered to inhibit OS progression by targeting glycolysis-related proteins. These potential inhibitors and natural products may be ideal candidates for the treatment of osteosarcoma following hundreds of preclinical and clinical trials. In this article, we explore key pathways, glycolysis enzymes, non-coding RNAs, inhibitors, and natural products regulating aerobic glycolysis in OS cells to gain a deeper understanding of the relationship between glycolysis and the progression of OS and discover novel therapeutic approaches targeting glycolytic metabolism in OS.
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6
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Liu C, Liu C, Fu R. Research progress on the role of PKM2 in the immune response. Front Immunol 2022; 13:936967. [PMID: 35967360 PMCID: PMC9365960 DOI: 10.3389/fimmu.2022.936967] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 07/04/2022] [Indexed: 11/22/2022] Open
Abstract
Pyruvate kinase (PK) is a key enzyme that catalyzes the dephosphorylation of phosphoenolpyruvate (PEP) into pyruvate, and is responsible for the production of ATP during glycolysis. As another important isozyme of PK, pyruvate kinase M2 (PKM2) exists in cells with high levels of nucleic acid synthesis, such as normal proliferating cells (e.g., lymphocytes and intestinal epithelial cells), embryonic cells, adult stem cells, and tumor cells. With further research, PKM2, as an important regulator of cellular pathophysiological activity, has attracted increasing attention in the process of autoimmune response and inflammatory. In this re]view, we examine the contribution of PKM2 to the human immune response. Further studies on the immune mechanisms of PKM2 are expected to provide more new ideas and drug targets for immunotherapy of inflammatory and autoimmune diseases, guiding drug development and disease treatment.
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Wang Z, Embaye KS, Yang Q, Qin L, Zhang C, Liu L, Zhan X, Zhang F, Wang X, Qin S. Development and validation of a novel epigenetic-related prognostic signature and candidate drugs for patients with lung adenocarcinoma. Aging (Albany NY) 2021; 13:18701-18717. [PMID: 34285141 PMCID: PMC8351720 DOI: 10.18632/aging.203315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 05/11/2021] [Indexed: 12/02/2022]
Abstract
Background: Epigenetic dysregulation has been increasingly proposed as a hallmark of cancer. Here, the aim of this study is to establish an epigenetic-related signature for predicting the prognosis of lung adenocarcinoma (LUAD) patients. Results: Five epigenetic-related genes (ERGs) (ARRB1, PARP1, PKM, TFDP1, and YWHAZ) were identified as prognostic hub genes and used to establish a prognostic signature. According our risk score system, LUAD patients were stratified into high and low risk groups, and patients in the high risk group had a worse prognosis. ROC analysis indicated that the signature was precise in predicting the prognosis. A new nomogram was constructed based on the five hub genes, which can predict the OS of every LUAD patients. The calibration curves showed that the nomogram had better accuracy in prediction. Finally, candidate drugs that aimed at hub ERGs were identified, which included 47 compounds. Conclusions: Our epigenetic-related signature nomogram can effectively and reliably predict OS of LUAD patients, also we provide precise targeted chemotherapeutic drugs. Methods: The genomic data and clinical data of LUAD cohort were downloaded from the TCGA database and ERGs were obtained from the EpiFactors database. GSE31210 and GSE50081 microarray datasets were included as independent external datasets. Univariate Cox, LASSO regression, and multivariate Cox analyses were applied to construct the epigenetic-related signature.
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Affiliation(s)
- Zhihao Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Kidane Siele Embaye
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qing Yang
- Department of Pharmacy, Hiser Medical Center of Qingdao, Qingdao 266033, China
| | - Lingzhi Qin
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chao Zhang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Liwei Liu
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaoqian Zhan
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Fengdi Zhang
- Department of Pathology, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 430030, China
| | - Xi Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shenghui Qin
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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8
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Wu D, Dasgupta A, Read AD, Bentley RET, Motamed M, Chen KH, Al-Qazazi R, Mewburn JD, Dunham-Snary KJ, Alizadeh E, Tian L, Archer SL. Oxygen sensing, mitochondrial biology and experimental therapeutics for pulmonary hypertension and cancer. Free Radic Biol Med 2021; 170:150-178. [PMID: 33450375 PMCID: PMC8217091 DOI: 10.1016/j.freeradbiomed.2020.12.452] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023]
Abstract
The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling molecule, hydrogen peroxide (H2O2), by superoxide dismutase (SOD2). H2O2 exits the mitochondria and regulates ion channels and enzymes, altering plasma membrane potential, intracellular Ca2+ and Ca2+-sensitization and controlling acute, adaptive, responses to hypoxia that involve changes in ventilation, vascular tone and neurotransmitter release. Subversion of this O2-sensing pathway creates a pseudohypoxic state that promotes disease progression in pulmonary arterial hypertension (PAH) and cancer. Pseudohypoxia is a state in which biochemical changes, normally associated with hypoxia, occur despite normal pO2. Epigenetic silencing of SOD2 by DNA methylation alters H2O2 production, activating hypoxia-inducible factor 1α, thereby disrupting mitochondrial metabolism and dynamics, accelerating cell proliferation and inhibiting apoptosis. Other epigenetic mechanisms, including dysregulation of microRNAs (miR), increase pyruvate dehydrogenase kinase and pyruvate kinase muscle isoform 2 expression in both diseases, favoring uncoupled aerobic glycolysis. This Warburg metabolic shift also accelerates cell proliferation and impairs apoptosis. Disordered mitochondrial dynamics, usually increased mitotic fission and impaired fusion, promotes disease progression in PAH and cancer. Epigenetic upregulation of dynamin-related protein 1 (Drp1) and its binding partners, MiD49 and MiD51, contributes to the pathogenesis of PAH and cancer. Finally, dysregulation of intramitochondrial Ca2+, resulting from impaired mitochondrial calcium uniporter complex (MCUC) function, links abnormal mitochondrial metabolism and dynamics. MiR-mediated decreases in MCUC function reduce intramitochondrial Ca2+, promoting Warburg metabolism, whilst increasing cytosolic Ca2+, promoting fission. Epigenetically disordered mitochondrial O2-sensing, metabolism, dynamics, and Ca2+ homeostasis offer new therapeutic targets for PAH and cancer. Promoting glucose oxidation, restoring the fission/fusion balance, and restoring mitochondrial calcium regulation are promising experimental therapeutic strategies.
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Affiliation(s)
- Danchen Wu
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Asish Dasgupta
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Austin D Read
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Rachel E T Bentley
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Mehras Motamed
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kuang-Hueih Chen
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Ruaa Al-Qazazi
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Jeffrey D Mewburn
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kimberly J Dunham-Snary
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Elahe Alizadeh
- Queen's Cardiopulmonary Unit (QCPU), Department of Medicine, Queen's University, 116 Barrie Street, Kingston, ON, K7L 3J9, Canada
| | - Lian Tian
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK
| | - Stephen L Archer
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada.
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Park JH, Kundu A, Lee SH, Jiang C, Lee SH, Kim YS, Kyung SY, Park SH, Kim HS. Specific Pyruvate Kinase M2 Inhibitor, Compound 3K, Induces Autophagic Cell Death through Disruption of the Glycolysis Pathway in Ovarian Cancer Cells. Int J Biol Sci 2021; 17:1895-1908. [PMID: 34131394 PMCID: PMC8193271 DOI: 10.7150/ijbs.59855] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/23/2021] [Indexed: 12/22/2022] Open
Abstract
Ovarian cancer is a common cause of death among gynecological cancers. Although ovarian cancer initially responds to chemotherapy, frequent recurrence in patients remains a therapeutic challenge. Pyruvate kinase M2 (PKM2) plays a pivotal role in regulating cancer cell survival. However, its therapeutic role remains unclear. Here, we investigated the anticancer effects of compound 3K, a specific PKM2 inhibitor, on the regulation of autophagic and apoptotic pathways in SK-OV-3 (PKM2-overexpressing human ovarian adenocarcinoma cell line). The anticancer effect of compound 3K was examined using MTT and colony formation assays in SK-OV-3 cells. PKM2 expression was positively correlated with the severity of the tumor, and expression of pro-apoptotic proteins increased in SK-OV-3 cells following compound 3K treatment. Compound 3K induced AMPK activation, which was accompanied by mTOR inhibition. Additionally, this compound inhibited glycolysis, resulting in reduced proliferation of SK-OV-3 cells. Compound 3K treatment suppressed tumor progression in an in vivo xenograft model. Our findings suggest that the inhibition of PKM2 by compound 3K affected the Warburg effect and induced autophagic cell death. Therefore, use of specific PKM2 inhibitors to block the glycolytic pathway and target cancer cell metabolism represents a promising therapeutic approach for treating PKM2-overexpressing ovarian cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Hyung Sik Kim
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
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Chen M, Liu H, Li Z, Ming AL, Chen H. Mechanism of PKM2 affecting cancer immunity and metabolism in Tumor Microenvironment. J Cancer 2021; 12:3566-3574. [PMID: 33995634 PMCID: PMC8120184 DOI: 10.7150/jca.54430] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 03/24/2021] [Indexed: 12/24/2022] Open
Abstract
PKM2 is the enzyme that regulates the final rate-limiting step of glycolysis. PKM2 expression can reinforce the utilization of oxygen and synthesis of growth substances in cancer cells by enhancing OXPHOS and the Warburg effect. In cancer immunity, PKM2 can modulate the expression of PD-L1 in M2 macrophage and decrease the amount and activity of CD8+ T cells. This affects cancer cell killing and immune escape sequentially. How PKM2 regulates PD-L1 expression through immunometabolism is summarized. PKM2 builds a bridge between energy metabolism and cancer immunity. The activator and inhibitor of PKM2 both promote the anti-cancer immune response and inhibit cancer growth and metastasis by regulating the metabolism of cancer cells and immune cells in the tumor microenvironment through HIF-1α/PKM2 pathway. This review focuses on the precise role of PKM2 modulating immunometabolism, providing valuable suggestions for further study in this field.
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Affiliation(s)
- Mengxi Chen
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P. R. China
| | - Huan Liu
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P. R. China
| | - Zhang Li
- Department of Pathology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, P. R. China
| | - Alex Lau Ming
- Department of Pathology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, P. R. China
| | - Honglei Chen
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, P. R. China
- Department of Pathology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, P. R. China
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11
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Choksi A, Parulekar A, Pant R, Shah VK, Nimma R, Firmal P, Singh S, Kundu GC, Shukla S, Chattopadhyay S. Tumor suppressor SMAR1 regulates PKM alternative splicing by HDAC6-mediated deacetylation of PTBP1. Cancer Metab 2021; 9:16. [PMID: 33863392 PMCID: PMC8052847 DOI: 10.1186/s40170-021-00252-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 03/30/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Highly proliferating cancer cells exhibit the Warburg effect by regulation of PKM alternative splicing and promoting the expression of PKM2. Majority of the alternative splicing events are known to occur in the nuclear matrix where various MARBPs actively participate in the alternative splicing events. SMAR1, being a MARBP and an important tumor suppressor, is known to regulate the splicing of various cancer-associated genes. This study focuses on the regulation of PKM alternative splicing and inhibition of the Warburg effect by SMAR1. METHODS Immunohistochemistry was performed in breast cancer patient samples to establish the correlation between SMAR1 and PKM isoform expression. Further, expression of PKM isoforms upon modulation in SMAR1 expression in breast cancer cell lines was quantified by qRT-PCR and western blot. The acetylation status of PTBP1 was estimated by immunoprecipitation along with its enrichment on PKM pre-mRNA by CLIP in SMAR1 knockdown conditions. The role of SMAR1 in tumor metabolism and tumorigenesis was explored by in vitro enzymatic assays and functional assays upon SMAR1 knockdown. Besides, in vivo tumor formation by injecting adeno-SMAR1-transduced MDA-MB-231 cells in NOD/SCID mice was performed. RESULTS The expression profile of SMAR1 and PKM isoforms in breast cancer patients revealed that SMAR1 has an inverse correlation with PKM2 and a positive correlation with PKM1. Further quantitative PKM isoform expression upon modulation in SMAR1 expression also reflects that SMAR1 promotes the expression of PKM1 over tumorigenic isoform PKM2. SMAR1 deacetylates PTBP1 via recruitment of HDAC6 resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. SMAR1 inhibits the Warburg effect, tumorigenic potential of cancer cells, and in vivo tumor generation in a PKM2-dependent manner. CONCLUSIONS SMAR1 regulates PKM alternative splicing by causing HDAC6-dependent deacetylation of PTBP1, resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. Additionally, SMAR1 suppresses glucose utilization and lactate production via repression of PKM2 expression. This suggests that tumor suppressor SMAR1 inhibits tumor cell metabolism and tumorigenic properties of cancer cells via regulation of PKM alternative splicing.
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Affiliation(s)
| | | | - Richa Pant
- National Centre for Cell Science, Pune, 411007, India
| | | | | | | | - Smriti Singh
- Indian Institute of Science Education and Research, Bhopal, 462066, India
| | - Gopal C Kundu
- National Centre for Cell Science, Pune, 411007, India.,Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, 751024, India
| | - Sanjeev Shukla
- Indian Institute of Science Education and Research, Bhopal, 462066, India
| | - Samit Chattopadhyay
- National Centre for Cell Science, Pune, 411007, India. .,Birla Institute of Technology and Science, Pilani - K K Birla Goa Campus, Goa, 403726, India.
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12
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Nandi S, Razzaghi M, Srivastava D, Dey M. Structural basis for allosteric regulation of pyruvate kinase M2 by phosphorylation and acetylation. J Biol Chem 2021; 295:17425-17440. [PMID: 33453989 DOI: 10.1074/jbc.ra120.015800] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/18/2020] [Indexed: 01/01/2023] Open
Abstract
Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme and transcriptional coactivator and is critical for tumor metabolism. In cancer cells, native tetrameric PKM2 is phosphorylated or acetylated, which initiates a switch to a dimeric/monomeric form that translocates into the nucleus, causing oncogene transcription. However, it is not known how these post-translational modifications (PTMs) disrupt the oligomeric state of PKM2. We explored this question via crystallographic and biophysical analyses of PKM2 mutants containing residues that mimic phosphorylation and acetylation. We find that the PTMs elicit major structural reorganization of the fructose 1,6-bisphosphate (FBP), an allosteric activator, binding site, impacting the interaction with FBP and causing a disruption in oligomerization. To gain insight into how these modifications might cause unique outcomes in cancer cells, we examined the impact of increasing the intracellular pH (pHi) from ∼7.1 (in normal cells) to ∼7.5 (in cancer cells). Biochemical studies of WT PKM2 (wtPKM2) and the two mimetic variants demonstrated that the activity decreases as the pH is increased from 7.0 to 8.0, and wtPKM2 is optimally active and amenable to FBP-mediated allosteric regulation at pHi 7.5. However, the PTM mimetics exist as a mixture of tetramer and dimer, indicating that physiologically dimeric fraction is important and might be necessary for the modified PKM2 to translocate into the nucleus. Thus, our findings provide insight into how PTMs and pH regulate PKM2 and offer a broader understanding of its intricate allosteric regulation mechanism by phosphorylation or acetylation.
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Affiliation(s)
- Suparno Nandi
- Department of Chemistry, University of Iowa, Iowa City, Iowa, USA
| | | | | | - Mishtu Dey
- Department of Chemistry, University of Iowa, Iowa City, Iowa, USA.
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13
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Huang J, Zhao X, Li X, Peng J, Yang W, Mi S. HMGCR inhibition stabilizes the glycolytic enzyme PKM2 to support the growth of renal cell carcinoma. PLoS Biol 2021; 19:e3001197. [PMID: 33905408 PMCID: PMC8104400 DOI: 10.1371/journal.pbio.3001197] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 05/07/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023] Open
Abstract
Renal cell carcinoma (RCC) is responsible for most cases of the kidney cancer. Previous research showed that low serum levels of cholesterol level positively correlate with poorer RCC-specific survival outcomes. However, the underlying mechanisms and functional significance of the role of cholesterol in the development of RCC remain obscure. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) plays a pivotal role in RCC development as it is the key rate-limiting enzyme of the cholesterol biosynthetic pathway. In this study, we demonstrated that the inhibition of HMGCR could accelerate the development of RCC tumors by lactate accumulation and angiogenesis in animal models. We identified that the inhibition of HMGCR led to an increase in glycolysis via the regulated HSP90 expression levels, thus maintaining the levels of a glycolysis rate-limiting enzyme, pyruvate kinase M2 (PKM2). Based on these findings, we reversed the HMGCR inhibition-induced tumor growth acceleration in RCC xenograft mice by suppressing glycolysis. Furthermore, the coadministration of Shikonin, a potent PKM2 inhibitor, reverted the tumor development induced by the HMGCR signaling pathway.
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Affiliation(s)
- Jiajun Huang
- Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, China
| | - Xiaoyu Zhao
- Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, China
| | - Xiang Li
- Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, China
| | - Jiwei Peng
- Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, China
| | - Weihao Yang
- Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, China
| | - Shengli Mi
- Bio-manufacturing Engineering Laboratory, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong, China
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14
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Chen X, Chen S, Yu D. Protein kinase function of pyruvate kinase M2 and cancer. Cancer Cell Int 2020; 20:523. [PMID: 33292198 PMCID: PMC7597019 DOI: 10.1186/s12935-020-01612-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 10/20/2020] [Indexed: 02/07/2023] Open
Abstract
Pyruvate kinase is a terminal enzyme in the glycolytic pathway, where it catalyzes the conversion of phosphoenolpyruvate to pyruvate and production of ATP via substrate level phosphorylation. PKM2 is one of four isoforms of pyruvate kinase and is widely expressed in many types of tumors and associated with tumorigenesis. In addition to pyruvate kinase activity involving the metabolic pathway, increasing evidence demonstrates that PKM2 exerts a non-metabolic function in cancers. PKM2 has been shown to be translocated into nucleus, where it serves as a protein kinase to phosphorylate various protein targets and contribute to multiple physiopathological processes. We discuss the nuclear localization of PKM2, its protein kinase function and association with cancers, and regulation of PKM2 activity.
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Affiliation(s)
- Xun Chen
- Department of Oral and Maxillofacial Surgery, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, 56 Lingyuan West Road, Guangzhou, 510055, People's Republic of China
| | - Shangwu Chen
- Department of Biochemistry, Guangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, People's Republic of China.
| | - Dongsheng Yu
- Department of Oral and Maxillofacial Surgery, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, 56 Lingyuan West Road, Guangzhou, 510055, People's Republic of China.
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15
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Nandi S, Dey M. Biochemical and structural insights into how amino acids regulate pyruvate kinase muscle isoform 2. J Biol Chem 2020; 295:5390-5403. [PMID: 32144209 PMCID: PMC7170521 DOI: 10.1074/jbc.ra120.013030] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/03/2020] [Indexed: 12/12/2022] Open
Abstract
Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.
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Affiliation(s)
- Suparno Nandi
- Department of Chemistry, University of Iowa, Iowa City, Iowa 52242
| | - Mishtu Dey
- Department of Chemistry, University of Iowa, Iowa City, Iowa 52242.
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16
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Isidor MS, Winther S, Markussen LK, Basse AL, Quistorff B, Nedergaard J, Emanuelli B, Hansen JB. Pyruvate kinase M2 represses thermogenic gene expression in brown adipocytes. FEBS Lett 2019; 594:1218-1225. [PMID: 31823361 DOI: 10.1002/1873-3468.13716] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 11/16/2019] [Accepted: 12/02/2019] [Indexed: 12/30/2022]
Abstract
Utilizing the thermogenic capacity of brown adipose tissue is a potential anti-obesity strategy; therefore, the mechanisms controlling expression of thermogenesis-related genes are of interest. Pyruvate kinase (PK) catalyzes the last step of glycolysis and exists as four isoenzymes: PK, liver, PK, red blood cell, PK, muscle (PKM1 and PKM2). PKM2 has both glycolytic and nuclear functions. Here, we report that PKM2 is enriched in brown adipose compared with white adipose tissue. Specific knockdown of PKM2 in mature brown adipocytes demonstrates that silencing of PKM2 does not lead to a decrease in PK activity, but causes a robust upregulation of thermogenic uncoupling protein 1 (Ucp1) and fibroblast growth factor 21 (Fgf21) gene expression. This increase is not mediated by any of the known mechanisms for PKM2-regulated gene expression, thus implying the existence of a novel mechanism for PKM2-dependent effects on gene expression.
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Affiliation(s)
- Marie S Isidor
- Department of Biology, University of Copenhagen, Denmark.,Department of Biomedical Sciences, University of Copenhagen, Denmark.,Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Sweden.,Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark
| | - Sally Winther
- Department of Biology, University of Copenhagen, Denmark
| | | | - Astrid L Basse
- Department of Biology, University of Copenhagen, Denmark
| | - Bjørn Quistorff
- Department of Biomedical Sciences, University of Copenhagen, Denmark
| | - Jan Nedergaard
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Sweden
| | - Brice Emanuelli
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark
| | - Jacob B Hansen
- Department of Biology, University of Copenhagen, Denmark
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17
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Chen J, Zhou Q, Feng J, Zheng W, Du J, Meng X, Wang Y, Wang J. Activation of AMPK promotes thyroid cancer cell migration through its interaction with PKM2 and β-catenin. Life Sci 2019; 239:116877. [PMID: 31669575 DOI: 10.1016/j.lfs.2019.116877] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 09/03/2019] [Accepted: 09/13/2019] [Indexed: 12/13/2022]
Abstract
AMP-activated protein kinase (AMPK) is induced by the exhaustion of cellular energy and activates adaptive alterations in cellular metabolism, which is the basis for cell survival during different environmental stresses. We aimed to investigate the biological functions of AMPK and its molecular mechanism in regulating thyroid cancer (TC) progression. In current study, we found that activation of AMPK by multiple agonists suppresses TC cell proliferation. However, AMPK activation also led to TC cell migration at the same time. Depletion of AMPK abolished the effect of its agonist on cell multiplication and migration. Mechanistic investigations revealed that the impact of AMPK in terms of cell migration is dependent on its nuclear translocation, since site mutation of AMPK in its nuclear translocation domain (K244A) abolished TC cell migration but did not affect the inhibition of cell proliferation by AMPK agonist. Moreover, the nuclear AMPK recruits PKM2 and β-catenin by their interaction, which promotes the transcription of cell migration related genes, including MMP7 and c-Myc. Furthermore, depletion of PKM2/β-catenin abolished the migration effect of AMPK agonists, but did not affect their effects on suppression of cell proliferation. Our results provided a novel function of AMPK in cancer migration, and suggested that a combination of AMPK activation and PKM2 depletion or inhibition can be a new strategy to achieve better therapeutic effects for TC patients.
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Affiliation(s)
- Jun Chen
- Department of Head and Neck Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Qinyi Zhou
- Department of Head and Neck Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Jialin Feng
- Department of Head and Neck Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Wenjie Zheng
- Department of Head and Neck Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Jing Du
- Department of Ultrasound, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Xiangchao Meng
- Department of Bone and Joint Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - You Wang
- Department of Bone and Joint Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Jiadong Wang
- Department of Head and Neck Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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18
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Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res 2019; 150:104511. [DOI: 10.1016/j.phrs.2019.104511] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 10/19/2019] [Accepted: 10/23/2019] [Indexed: 12/24/2022]
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19
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Su Q, Luo S, Tan Q, Deng J, Zhou S, Peng M, Tao T, Yang X. The role of pyruvate kinase M2 in anticancer therapeutic treatments. Oncol Lett 2019; 18:5663-5672. [PMID: 31788038 PMCID: PMC6865080 DOI: 10.3892/ol.2019.10948] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 09/06/2019] [Indexed: 12/13/2022] Open
Abstract
Cancer cells are characterized by a high glycolytic rate, which leads to energy regeneration and anabolic metabolism; a consequence of this is the abnormal expression of pyruvate kinase isoenzyme M2 (PKM2). Multiple studies have demonstrated that the expression levels of PKM2 are upregulated in numerous cancer types. Consequently, the mechanism of action of certain anticancer drugs is to downregulate PKM2 expression, indicating the significance of PKM2 in a chemotherapeutic setting. Furthermore, it has previously been highlighted that the downregulation of PKM2 expression, using either inhibitors or short interfering RNA, enhances the anticancer effect exerted by THP treatment on bladder cancer cells, both in vitro and in vivo. The present review summarizes the detailed mechanisms and therapeutic relevance of anticancer drugs that inhibit PKM2 expression. In addition, the relationship between PKM2 expression levels and drug resistance were explored. Finally, future directions, such as the targeting of PKM2 as a strategy to explore novel anticancer agents, were suggested. The current review explored and highlighted the important role of PKM2 in anticancer treatments.
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Affiliation(s)
- Qiongli Su
- Department of Pharmacy, Zhuzhou Central Hospital, Zhuzhou, Hunan 412000, P.R. China
| | - Shengping Luo
- Department of Pharmacy, Zhuzhou Central Hospital, Zhuzhou, Hunan 412000, P.R. China
| | - Qiuhong Tan
- Department of Pharmacy, Zhuzhou Central Hospital, Zhuzhou, Hunan 412000, P.R. China
| | - Jun Deng
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P.R. China
| | - Sichun Zhou
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P.R. China
| | - Mei Peng
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Ting Tao
- Department of Pharmacy, Yueyang Maternal-Child Medicine Health Hospital, Yueyang, Hunan 414000, P.R. China
| | - Xiaoping Yang
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P.R. China
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20
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A critical review of the role of M 2PYK in the Warburg effect. Biochim Biophys Acta Rev Cancer 2019; 1871:225-239. [PMID: 30708038 PMCID: PMC6525063 DOI: 10.1016/j.bbcan.2019.01.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 01/14/2019] [Accepted: 01/14/2019] [Indexed: 12/17/2022]
Abstract
It is becoming generally accepted in recent literature that the Warburg effect in cancer depends on inhibition of M2PYK, the pyruvate kinase isozyme most commonly expressed in tumors. We remain skeptical. There continues to be a general lack of solid experimental evidence for the underlying idea that a bottle neck in aerobic glycolysis at the level of M2PYK results in an expanded pool of glycolytic intermediates (which are thought to serve as building blocks necessary for proliferation and growth of cancer cells). If a bottle neck at M2PYK exists, then the remarkable increase in lactate production by cancer cells is a paradox, particularly since a high percentage of the carbons of lactate originate from glucose. The finding that pyruvate kinase activity is invariantly increased rather than decreased in cancer undermines the logic of the M2PYK bottle neck, but is consistent with high lactate production. The "inactive" state of M2PYK in cancer is often described as a dimer (with reduced substrate affinity) that has dissociated from an active tetramer of M2PYK. Although M2PYK clearly dissociates easier than other isozymes of pyruvate kinase, it is not clear that dissociation of the tetramer occurs in vivo when ligands are present that promote tetramer formation. Furthermore, it is also not clear whether the dissociated dimer retains any activity at all. A number of non-canonical functions for M2PYK have been proposed, all of which can be challenged by the finding that not all cancer cell types are dependent on M2PYK expression. Additional in-depth studies of the Warburg effect and specifically of the possible regulatory role of M2PYK in the Warburg effect are needed.
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21
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Chen JJ, Schmucker LN, Visco DP. Virtual high-throughput screens identifying hPK-M2 inhibitors: Exploration of model extrapolation. Comput Biol Chem 2019; 78:317-329. [PMID: 30623877 DOI: 10.1016/j.compbiolchem.2018.12.006] [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: 10/16/2018] [Revised: 12/11/2018] [Accepted: 12/13/2018] [Indexed: 10/27/2022]
Abstract
Glycolysis with PK-M2 occurs typically in anaerobic conditions and atypically in aerobic conditions, which is known as the Warburg effect. The Warburg effect is found in many oncogenic situations and is believed to provide energy and biomass for oncogenesis to persist. The work presented targets human PK-M2 (hPK-M2) in a virtual high-throughput screen to identify new inhibitors and leads for further study. In the initial screen, one of the 12 candidates selected for experimental validation showed biological activity (hit-rate = 8.13%). In the second screen with retrained models, six of 11 candidates selected for experimental validation showed biological activity (hit-rate: 54.5%). Additionally, four different scaffolds were identified for further analysis when examining the tested candidates and compounds in the training data. Finally, extrapolation was necessary to identify a sufficient number of candidates to test in the second screen. Examination of the results suggested stepwise extrapolation to maximize efficiency.
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Affiliation(s)
- Jonathan J Chen
- Department of Biology, The University of Akron, 302 Buchtel Common, Akron, OH 44325, USA.
| | - Lyndsey N Schmucker
- Department of Chemical and Biomolecular Engineering, The University of Akron, 302 Buchtel Common, Akron, OH 44325, USA.
| | - Donald P Visco
- Department of Chemical and Biomolecular Engineering, The University of Akron, 302 Buchtel Common, Akron, OH 44325, USA.
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22
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Liu M, Zhang Z, Wang H, Chen X, Jin C. Activation of AMPK by metformin promotes renal cancer cell proliferation under glucose deprivation through its interaction with PKM2. Int J Biol Sci 2019; 15:617-627. [PMID: 30745848 PMCID: PMC6367591 DOI: 10.7150/ijbs.29689] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 10/31/2018] [Indexed: 01/03/2023] Open
Abstract
Metformin, a common therapeutics for type 2 diabetics, was recently demonstrated to possess antitumor activity in various cancer types. However, its therapy effect in renal cell carcinoma (RCC) still remains controversial. In this study, we found that metformin treatment in RCC cells lead to activation of AMPK, which suppressed the cell proliferation under normal condition, but enhanced cell proliferation under glucose deprivation (GD) condition. Depletion of AMPK by siRNA abolished the proliferation effect of MF under GD condition. Mechanistic investigations revealed that the effect of AMPK on cell proliferation under GD condition is dependent on its nuclear translocation. Moreover, the nuclear AMPK recruits PKM2 and β-Catenin to form a complex, which promotes the transcription of cell proliferation related genes, including CCND1 and c-Myc. Furthermore, depletion of PKM2 or β-Catenin abrogated the proliferative effects of metformin under GD condition. And inhibition of PKM2 also re-sensitized the A498 xenograft in response to metformin treatment. Together, our results suggested that combined of AMPK activation and PKM2 depletion or inhibition can achieve better therapeutic effect for RCC patients.
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Affiliation(s)
- Meihan Liu
- Department of Ultrasonography, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Zhuo Zhang
- Department of Urology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Hui Wang
- Department of Ultrasonography, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Xiaoliang Chen
- Department of Urology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Chunxiang Jin
- Department of Ultrasonography, China-Japan Union Hospital, Jilin University, Changchun, China
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23
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Li RZ, Fan XX, Shi DF, Zhu GY, Wang YW, Luo LX, Pan HD, Yao XJ, Leung ELH, Liu L. Identification of a new pyruvate kinase M2 isoform (PKM2) activator for the treatment of non-small-cell lung cancer (NSCLC). Chem Biol Drug Des 2018; 92:1851-1858. [PMID: 29931766 DOI: 10.1111/cbdd.13354] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/11/2018] [Accepted: 05/19/2018] [Indexed: 12/11/2022]
Abstract
Lung cancer is the number one cancer in terms of both mortality and incidence. Cancer cells differ from normal cells in that they can reprogram their metabolism to support a rapid proliferation rate and alter oxidative phosphorylation processes toward lactic acid fermentation, even under aerobic conditions. Therefore, we aimed to identify new compounds that might act as pyruvate kinase M2 isoform (PKM2) activators and to investigate their anti-cancer efficacy in non-small-cell lung cancer (NSCLC) cells. The molecular docking method was applied to screen PKM2 activators from our virtual natural products library. Then, compounds with promising docking scores were examined for cytotoxic effects in a panel of NSCLC cells using the MTT assay. Functional effects and therapeutic mechanisms were investigated by in vitro enzyme assays, western blotting (WB), and flow cytometry. Molecular docking showed that 0089-0022 acts as a potential PKM2 activator by binding to the kinase pocket. An in vitro enzyme activity assay showed that 0089-0022 is a direct PKM2 activator and that it effectively induces apoptosis in A549 and H1975 cells through inhibition of AKT phosphorylation. Our results suggest that 0089-0022 activates PKM2 and thus is a promising anti-cancer therapeutic candidate in NSCLC.
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Affiliation(s)
- Run-Ze Li
- State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
| | - Xing-Xing Fan
- State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
| | - Dan-Feng Shi
- College of Chemistry and Chemical Engineering and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, China
| | - Guo-Yuan Zhu
- State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
| | - Yu-Wei Wang
- State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
| | - Lian-Xiang Luo
- State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
| | - Hu-Dan Pan
- State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
| | - Xiao-Jun Yao
- State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
- College of Chemistry and Chemical Engineering and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, China
| | - Elaine Lai-Han Leung
- State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
- Respiratory Medicine Department, Taihe Hospital, Hubei University of Medicine, Hubei, China
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
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Wang Y, Hao F, Nan Y, Qu L, Na W, Jia C, Chen X. PKM2 Inhibitor Shikonin Overcomes the Cisplatin Resistance in Bladder Cancer by Inducing Necroptosis. Int J Biol Sci 2018; 14:1883-1891. [PMID: 30443191 PMCID: PMC6231221 DOI: 10.7150/ijbs.27854] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 09/08/2018] [Indexed: 02/06/2023] Open
Abstract
Cisplatin-based chemotherapy often results in the development of chemo-resistance when used to treat bladder cancer (BC), which is difficult to overcome. Recent data indicate that pyruvate kinase M2 (PKM2), a glycolytic enzyme for Warburg effect, is strongly upregulated in BC, and contributes to the cisplatin resistance in BC. However, the underlying mechanisms remain unclear. In this study, we also found that the expression level of PKM2 is also higher in cisplatin resistant BC cells and tumors. Down-regulation of PKM2 by siRNA or inhibition of PKM2 by shikonin re-sensitized the cisplatin resistant T24 cells. Shikonin and cisplatin together exhibit significantly greater killing effects than when used alone. Interestingly, we found shikonin kills the T24 cisplatin resistant cells by inducing necroptosis, as the cell death could not inhibited by apoptosis inhibitor, z-VAD, but compromised by RIP3 inhibitor, GSK872, or RIP3 siRNA. In contrast, shikonin induced apoptosis in T24 parental cells. We further investigate the underlying mechanism, and found that the dysregulation of Bcl-2 family proteins, including Bcl-2, PUMA, Bax, play an important role in deciding that shikonin kills the BC cells by necroptosis or apoptosis. Collectively, our results suggested that inducing necroptosis is an alternative way to overcome the apoptosis resistant in BC therapy, and orchestrating the regulation of Bcl-2, PUMA, and Bax in BC cisplatin resistant cells may improve the therapy effect of cisplatin in BC tumor.
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Affiliation(s)
- Yonggang Wang
- Department of Urology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Fangshi Hao
- Department of Urology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Yonghao Nan
- Department of Urology, The Frist Affiliated Hospital of Zhengzhou University, Zhengzhou
| | - Licheng Qu
- Center for Reproductive Medicine and Center for Prenatal Diagnosis, First Hospital, Jilin University, Changchun, China
| | - Wanli Na
- Department of Urology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Chunshu Jia
- Center for Reproductive Medicine and Center for Prenatal Diagnosis, First Hospital, Jilin University, Changchun, China
| | - Xiaoliang Chen
- Department of Urology, China-Japan Union Hospital, Jilin University, Changchun, China
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25
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Yoon YJ, Kim YH, Jin Y, Chi SW, Moon JH, Han DC, Kwon BM. 2′-hydroxycinnamaldehyde inhibits cancer cell proliferation and tumor growth by targeting the pyruvate kinase M2. Cancer Lett 2018; 434:42-55. [DOI: 10.1016/j.canlet.2018.07.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 06/20/2018] [Accepted: 07/09/2018] [Indexed: 12/29/2022]
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26
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Marbaniang C, Kma L. Dysregulation of Glucose Metabolism by Oncogenes and Tumor Suppressors in Cancer Cells. Asian Pac J Cancer Prev 2018; 19:2377-2390. [PMID: 30255690 PMCID: PMC6249467 DOI: 10.22034/apjcp.2018.19.9.2377] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 08/20/2018] [Indexed: 02/07/2023] Open
Abstract
Cancers are complex diseases having several unique features, commonly described as ‘hallmarks of cancer’. Among them, altered signaling pathways are the common characteristic features that drive cancer progression; this is achieved due to mutations that lead to the activation of growth promoting(s) oncogenes and inactivation of tumor suppressors. As a result of which, cancer cells increase their glycolytic rate by consuming a large amount of glucose, and convert a majority of glucose to lactate even in the presence of oxygen known as the “Warburg effect”. Tumor cells like other cells are strictly dependent on energy for growth and survival; therefore, understanding energy metabolism will give us an idea to develop new effective anti-cancer therapies that target cancer energy production pathways. This review summarizes the roles of tumor suppressors and oncogenes and their products that provide metabolic advantages to cancer cells which in turn leads to the establishment of the “Warburg effect” and ultimately leads to cancer progression. Understanding cancer cell’s vulnerability will provide potential targets for its control.
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Affiliation(s)
- Casterland Marbaniang
- Department of Biochemistry, Cancer and Radiation Countermeasures Unit,North-Eastern Hill University, Shillong, Meghalaya, India.
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27
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El-Abd E, El-Sheikh M, Zaky S, Fayed W, El-Zoghby S. Plasma TuM2-PK correlates with tumor size, CRP and CA 15-3 in metastatic breast carcinomas; short versus long term follow up study of the Egyptian breast cancer patients. Cancer Biomark 2018; 20:123-133. [PMID: 28869444 DOI: 10.3233/cbm-160482] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND The key regulator of tumor metabolome is the glycolytic isoenzyme M2-PK which favors the generation of nucleic acid via glutaminolysis as hypoxic adaptive mechanism in the tumor cells. AIM The study aimed to evaluate the prognostic role of M2-PK, CRP, and CA 15-3 in preoperative and metastatic breast carcinomas. PATIENTS AND METHODS The study included 70 females; 15 controls, 33 preoperative primary breast carcinomas clinically metastasis free, and 22 clinically diagnosed metastatic breast carcinomas. M2-PK and CA 15-3 were detected by ELISA. CRP was quantified using the CRP LATEX kit. RESULTS TuM2-PK significantly increased in metastatic and preoperative groups when compared to controls (p= 0.049, p= 0.001); respectively. Both CRP and CA 15-3 were significantly increased in metastatic than the preoperative group (p= 0.002). CA 15-3 was significantly increased in both groups when compared to controls (p= 0.016; p< 0.001; respectively). TuM2-PK level significantly related to tumor size in metastatic group (p= 0.006) and with menstruation status (p= 0.039), and liver metastasis (p= 0.036) in preoperative group. TuM2-PK significantly correlated with CRP (r= 0.793, p= 0.004), and CA 15-3 (r= 0.568, p= 0.006) in the metastatic group.Metastatic group with TuM2-PK ⩽ 15 U/ml had significantly higher survival rate than those with > 15 U/ml (χ2= 13.841, p< 0.001) within 3.3-4.2 but not after 10-20 years follow up period. Metastasis to bone and lymph nodes significantly increased in the metastatic than the preoperative group (p= 0.002, p= 0.013; respectively). Within 3.3-4.2 years, CA15.3 has the highest prognostic performance in metastatic group while both TuM2-PK and CRP have same specificity. On the other hand, TuM2-PK has the highest prognostic performance in preoperative group. After 20 years follow up period, there was neither significant difference in the performance of the three markers in predicting mortality in metastatic and preoperative groups nor in predicting metastasis in preoperative group. CONCLUSION Current results document for the first time, a cross-talk between TuM2-PK and each of CRP and CA 15-3 in metastatic breast cancer.
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Affiliation(s)
- Eman El-Abd
- Radiation Sciences Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.,Molecular Biology Department, Medical Technology Centre, MRI, Alexandria University, Alexandria, Egypt
| | - Marwa El-Sheikh
- Medical Applied Chemistry, MRI, Alexandria University, Alexandria, Egypt
| | - Sameh Zaky
- Cancer Management and Research, MRI, Alexandria University, Alexandria, Egypt
| | - Wagdy Fayed
- Experimental and Clinical Surgery, MRI, Alexandria University, Alexandria, Egypt
| | - Safinaz El-Zoghby
- Medical Applied Chemistry, MRI, Alexandria University, Alexandria, Egypt
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28
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Hsu MC, Hung WC. Pyruvate kinase M2 fuels multiple aspects of cancer cells: from cellular metabolism, transcriptional regulation to extracellular signaling. Mol Cancer 2018; 17:35. [PMID: 29455645 PMCID: PMC5817853 DOI: 10.1186/s12943-018-0791-3] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 02/01/2018] [Indexed: 12/11/2022] Open
Abstract
Originally identified as a metabolic enzyme that catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP in the glycolytic pathway, pyruvate kinase M2-type (PKM2) has been shown to exhibit novel biological activities in the nucleus and outside the cells. Although cell-based studies reveal new non-canonical functions of PKM2 in gene transcription, epigenetic modulation and cell cycle progression, the importance of these non-canonical functions in PKM2-mediated tumorigenesis is still under debate because studies in genetically modified mice do not consistently echo the findings observed in cultured cancer cells. In addition to regulation of gene expression, the existence of PKM2 in exosomes opens a new venue to study the potential role of this glycolytic enzyme in cell-cell communication and extracellular signal initiation. In this review, we briefly summarize current understanding of PKM2 in metabolic switch and gene regulation. We will then emphasize recent progress of PKM2 in extracellular signaling and tumor microenvironment reprogramming. Finally, the discrepancy of some PKM2’s functions in vitro and in vivo, and the application of PKM2 in cancer detection and treatment will be discussed.
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Affiliation(s)
- Ming-Chuan Hsu
- National Institute of Cancer Research, National Health Research Institutes, No. 367, Shengli Road, Tainan, 704, Taiwan
| | - Wen-Chun Hung
- National Institute of Cancer Research, National Health Research Institutes, No. 367, Shengli Road, Tainan, 704, Taiwan. .,Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 802, Taiwan.
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29
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Yu L, Chen X, Wang L, Chen S. The sweet trap in tumors: aerobic glycolysis and potential targets for therapy. Oncotarget 2018; 7:38908-38926. [PMID: 26918353 PMCID: PMC5122440 DOI: 10.18632/oncotarget.7676] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 02/16/2016] [Indexed: 12/11/2022] Open
Abstract
Metabolic change is one of the hallmarks of tumor, which has recently attracted a great of attention. One of main metabolic characteristics of tumor cells is the high level of glycolysis even in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. The energy production is much less in glycolysis pathway than that in tricarboxylic acid cycle. The molecular mechanism of a high glycolytic flux in tumor cells remains unclear. A large amount of intermediates derived from glycolytic pathway could meet the biosynthetic requirements of the proliferating cells. Hypoxia-induced HIF-1α, PI3K-Akt-mTOR signaling pathway, and many other factors, such as oncogene activation and tumor suppressor inactivation, drive cancer cells to favor glycolysis over mitochondrial oxidation. Several small molecules targeting glycolytic pathway exhibit promising anticancer activity both in vitro and in vivo. In this review, we will focus on the latest progress in the regulation of aerobic glycolysis and discuss the potential targets for the tumor therapy.
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Affiliation(s)
- Li Yu
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Xun Chen
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, P.R. China
| | - Liantang Wang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
| | - Shangwu Chen
- State Key Laboratory for Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen (Zhongshan) University, Guangzhou, P.R. China
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30
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Immunogenicity of mammary tumor cells can be induced by shikonin via direct binding-interference with hnRNPA1. Oncotarget 2017; 7:43629-43653. [PMID: 27248319 PMCID: PMC5190049 DOI: 10.18632/oncotarget.9660] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 05/13/2016] [Indexed: 12/13/2022] Open
Abstract
Immunogenic cell death (ICD) of tumor cells occurs via various pathways that activate immune cell systems against cancer. Previous studies have demonstrated that shikonin (SK), a plant secondary metabolite, can confer strong pharmacological activities that activate ICD and strong immunogenicity of tumor cells. However, the exact hierarchical regulatory mechanisms including the molecular targets of SK-activated immunogenicity are still unknown. Here, the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was revealed to serve as a specific protein target for SK. This binding plays a key role in SK-stimulated ICD activity and the suppression of post-transcriptional mRNA processing, including nuclear export activity of newly synthesized mRNAs in mammary carcinoma cells in vitro. Moreover, it also mechanistically mediates the anti-metastatic effect of a tumor cell lysate (TCL) vaccine, which can be readily generated from SK-treated 4T1 tumor cells (SK-TCL), and the derived tumor-immunogenicity of SK-TCL-treated dendritic cells in vivo. Together, the identification of hnRNPA1 as the intracellular molecular target provides compelling pharmacology-based knowledge for the potential clinical use of SK-induced immunogenicity. In addition, SK may also serve as a potent suppressor that interferes with specific post-transcriptional activities, a mechanism which may be useful for exploitation in cancer therapeutics.
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31
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Modulation of GLO1 Expression Affects Malignant Properties of Cells. Int J Mol Sci 2016; 17:ijms17122133. [PMID: 27999356 PMCID: PMC5187933 DOI: 10.3390/ijms17122133] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 12/08/2016] [Accepted: 12/12/2016] [Indexed: 12/25/2022] Open
Abstract
The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect) characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO). Consequently, the rate of detoxification of this reactive glycolytic byproduct needs to be increased in order to prevent deleterious effects to the cells. This is brought about by an increased expression of glyoxalase 1 (GLO1) that is the rate-limiting enzyme of the MGO-detoxifying glyoxalase system. Here, we overexpressed GLO1 in HEK 293 cells and silenced it in MCF-7 cells using shRNA. Tumor-related properties of wild type and transformed cells were compared and key glycolytic enzyme activities assessed. Furthermore, the cells were subjected to hypoxic conditions to analyze the impact on cell proliferation and enzyme activities. Our results demonstrate that knockdown of GLO1 in the cancer cells significantly reduced tumor-associated properties such as migration and proliferation, whereas no functional alterations where found by overexpression of GLO1 in HEK 293 cells. In contrast, hypoxia caused inhibition of cell growth of all cells except of those overexpressing GLO1. Altogether, we conclude that GLO1 on one hand is crucial to maintaining tumor characteristics of malignant cells, and, on the other hand, supports malignant transformation of cells in a hypoxic environment when overexpressed.
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32
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Wang H, Zhang H, Deng P, Liu C, Li D, Jie H, Zhang H, Zhou Z, Zhao YL. Tissue metabolic profiling of human gastric cancer assessed by (1)H NMR. BMC Cancer 2016; 16:371. [PMID: 27356757 PMCID: PMC4928316 DOI: 10.1186/s12885-016-2356-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 05/11/2016] [Indexed: 02/05/2023] Open
Abstract
Background Gastric cancer is the fourth most common cancer and the second most deadly cancer worldwide. Study on molecular mechanisms of carcinogenesis will play a significant role in diagnosing and treating gastric cancer. Metabolic profiling may offer the opportunity to understand the molecular mechanism of carcinogenesis and help to identify the potential biomarkers for the early diagnosis of gastric cancer. Methods In this study, we reported the metabolic profiling of tissue samples on a large cohort of human gastric cancer subjects (n = 125) and normal controls (n = 54) based on 1H nuclear magnetic resonance (1H NMR) together with multivariate statistical analyses (PCA, PLS-DA, OPLS-DA and ROC curve). Results The OPLS-DA model showed adequate discrimination between cancer tissues and normal controls, and meanwhile, the model excellently discriminated the stage-related of tissue samples (stage I, 30; stage II, 46; stage III, 37; stage IV, 12) and normal controls. A total of 48 endogenous distinguishing metabolites (VIP > 1 and p < 0.05) were identified, 13 of which were changed with the progression of gastric cancer. These modified metabolites revealed disturbance of glycolysis, glutaminolysis, TCA, amino acids and choline metabolism, which were correlated with the occurrence and development of human gastric cancer. The receiver operating characteristic diagnostic AUC of OPLS-DA model between cancer tissues and normal controls was 0.945. And the ROC curves among different stages cancer subjects and normal controls were gradually improved, the corresponding AUC values were 0.952, 0.994, 0.998 and 0.999, demonstrating the robust diagnostic power of this metabolic profiling approach. Conclusion As far as we know, the present study firstly identified the differential metabolites in various stages of gastric cancer tissues. And the AUC values were relatively high. So these results suggest that the metabolic profiling of gastric cancer tissues has great potential in detecting this disease and helping to understand its underlying metabolic mechanisms. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2356-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Huijuan Wang
- College of Medicine, Henan University, Kaifeng, 475004, Henan, China.,State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, People's Republic of China
| | - Hailong Zhang
- College of Medicine, Henan University, Kaifeng, 475004, Henan, China.,State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, People's Republic of China
| | - Pengchi Deng
- Analytical & Testing Center, Sichuan University, Chengdu, 610041, China
| | - Chunqi Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, People's Republic of China
| | - Dandan Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, People's Republic of China
| | - Hui Jie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, People's Republic of China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
| | - Zongguang Zhou
- Department of Gastrointestinal surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
| | - Ying-Lan Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, People's Republic of China.
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Chan AKC, Bruce JIE, Siriwardena AK. Glucose metabolic phenotype of pancreatic cancer. World J Gastroenterol 2016; 22:3471-3485. [PMID: 27022229 PMCID: PMC4806205 DOI: 10.3748/wjg.v22.i12.3471] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 01/30/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To construct a global “metabolic phenotype” of pancreatic ductal adenocarcinoma (PDAC) reflecting tumour-related metabolic enzyme expression.
METHODS: A systematic review of the literature was performed using OvidSP and PubMed databases using keywords “pancreatic cancer” and individual glycolytic and mitochondrial oxidative phosphorylation (MOP) enzymes. Both human and animal studies investigating the oncological effect of enzyme expression changes and inhibitors in both an in vitro and in vivo setting were included in the review. Data reporting changes in enzyme expression and the effects on PDAC cells, such as survival and metastatic potential, were extracted to construct a metabolic phenotype.
RESULTS: Seven hundred and ten papers were initially retrieved, and were screened to meet the review inclusion criteria. 107 unique articles were identified as reporting data involving glycolytic enzymes, and 28 articles involving MOP enzymes in PDAC. Data extraction followed a pre-defined protocol. There is consistent over-expression of glycolytic enzymes and lactate dehydrogenase in keeping with the Warburg effect to facilitate rapid adenosine-triphosphate production from glycolysis. Certain isoforms of these enzymes were over-expressed specifically in PDAC. Altering expression levels of HK, PGI, FBA, enolase, PK-M2 and LDA-A with metabolic inhibitors have shown a favourable effect on PDAC, thus identifying these as potential therapeutic targets. However, the Warburg effect on MOP enzymes is less clear, with different expression levels at different points in the Krebs cycle resulting in a fundamental change of metabolite levels, suggesting that other essential anabolic pathways are being stimulated.
CONCLUSION: Further characterisation of the PDAC metabolic phenotype is necessary as currently there are few clinical studies and no successful clinical trials targeting metabolic enzymes.
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Shen Y, Chen M, Huang S, Zou X. Pantoprazole inhibits human gastric adenocarcinoma SGC-7901 cells by downregulating the expression of pyruvate kinase M2. Oncol Lett 2015; 11:717-722. [PMID: 26870273 DOI: 10.3892/ol.2015.3912] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 10/09/2015] [Indexed: 01/14/2023] Open
Abstract
The Warburg effect is important in tumor growth. The human M2 isoform of pyruvate kinase (PKM2) is a key enzyme that regulates aerobic glycolysis in tumor cells. Recent studies have demonstrated that PKM2 is a potential target for cancer therapy. The present study investigated the effects of pantoprazole (PPZ) treatment and PKM2 transfection on human gastric adenocarcinoma SGC-7901 cells in vitro. The present study revealed that PPZ inhibited the proliferation of tumor cells, induced apoptosis and downregulated the expression of PKM2, which contributes to the current understanding of the functional association between PPZ and PKM2. In summary, PPZ may suppress tumor growth as a PKM2 protein inhibitor.
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Affiliation(s)
- Yonghua Shen
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Min Chen
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Shuling Huang
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu 210008, P.R. China
| | - Xiaoping Zou
- Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, Jiangsu 210008, P.R. China
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35
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Combined effect of microRNA, nutraceuticals and drug on pancreatic cancer cell lines. Chem Biol Interact 2015; 233:56-64. [DOI: 10.1016/j.cbi.2015.03.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 03/13/2015] [Accepted: 03/18/2015] [Indexed: 01/11/2023]
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Abstract
Reprogrammed metabolism is a key feature of cancer cells. The pyruvate kinase M2 (PKM2) isoform, which is commonly upregulated in many human cancers, has been recently shown to play a crucial role in metabolism reprogramming, gene transcription and cell cycle progression. In this Cell Science at a glance article and accompanying poster, we provide a brief overview of recent advances in understanding the mechanisms underlying the regulation of PKM2 expression, enzymatic activity, metabolic functions and subcellular location. We highlight the instrumental role of the non-metabolic functions of PKM2 in tumorigenesis and evaluate the potential to target PKM2 for cancer treatment.
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Affiliation(s)
- Weiwei Yang
- Key Laboratory of System Biology and Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhimin Lu
- Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
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37
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Li Z, Yang P, Li Z. The multifaceted regulation and functions of PKM2 in tumor progression. BIOCHIMICA ET BIOPHYSICA ACTA 2014; 1846:285-96. [PMID: 25064846 DOI: 10.1016/j.bbcan.2014.07.008] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 07/11/2014] [Accepted: 07/14/2014] [Indexed: 02/06/2023]
Abstract
Tumor cells undergo metabolic rewiring from oxidative phosphorylation towards aerobic glycolysis to maintain the increased anabolic requirements for cell proliferation. It is widely accepted that specific expression of the M2 type pyruvate kinase (PKM2) in tumor cells contributes to this aerobic glycolysis phenotype. To date, researchers have uncovered myriad forms of functional regulation for PKM2, which confers a growth advantage on the tumor cells to enable them to adapt to various microenvironmental signals. Here the richness of our understanding on the modulations and functions of PKM2 in tumor progression is reviewed, and some new insights into the paradoxical expression and functional differences of PKM2 in distinct cancer types are offered.
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Affiliation(s)
- Zongwei Li
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China
| | - Peng Yang
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China
| | - Zhuoyu Li
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan 030006, China; College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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38
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Meng MB, Wang HH, Guo WH, Wu ZQ, Zeng XL, Zaorsky NG, Shi HS, Qian D, Niu ZM, Jiang B, Zhao LJ, Yuan ZY, Wang P. Targeting pyruvate kinase M2 contributes to radiosensitivity of non-small cell lung cancer cells in vitro and in vivo. Cancer Lett 2014; 356:985-93. [PMID: 25444918 DOI: 10.1016/j.canlet.2014.11.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 09/17/2014] [Accepted: 11/09/2014] [Indexed: 02/05/2023]
Abstract
Aerobic glycolysis, a metabolic hallmark of cancer, is associated with radioresistance in non-small cell lung cancer (NSCLC). Pyruvate kinase M2 isoform (PKM2), a key regulator of glycolysis, is expressed exclusively in cancers. However, the impact of PKM2 silencing on the radiosensitivity of NSCLC has not been explored. Here, we show a plasmid of shRNA-PKM2 for expressing a short hairpin RNA targeting PKM2 (pshRNA-PKM2) and demonstrate that treatment with pshRNA-PKM2 effectively inhibits PKM2 expression in NSCLC cell lines and xenografts. Silencing of PKM2 expression enhanced ionizing radiation (IR)-induced apoptosis and autophagy in vitro and in vivo, accompanied by inhibiting AKT and PDK1 phosphorylation, but enhanced ERK and GSK3β phosphorylation. These results demonstrated that knockdown of PKM2 expression enhances the radiosensitivity of NSCLC cell lines and xenografts as well as may aid in the design of new therapies for the treatment of NSCLC.
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Affiliation(s)
- Mao-Bin Meng
- Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.
| | - Huan-Huan Wang
- Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Wen-Hao Guo
- Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China Clinical Medicine School, Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhi-Qiang Wu
- Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Xian-Liang Zeng
- Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Nicholas G Zaorsky
- Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | - Hua-Shan Shi
- Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China Clinical Medicine School, Sichuan University, Chengdu, Sichuan 610041, China
| | - Dong Qian
- Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Zhi-Min Niu
- Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Bo Jiang
- Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Lu-Jun Zhao
- Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Zhi-Yong Yuan
- Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
| | - Ping Wang
- Department of Radiation Oncology, CyberKnife Center, and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
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Li J, Yang Z, Zou Q, Yuan Y, Li J, Liang L, Zeng G, Chen S. PKM2 and ACVR 1C are prognostic markers for poor prognosis of gallbladder cancer. Clin Transl Oncol 2014; 16:200-7. [PMID: 23793810 DOI: 10.1007/s12094-013-1063-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 05/30/2013] [Indexed: 12/21/2022]
Abstract
PURPOSE To identify biological markers related to the progression and prognosis of GBC. METHODS The expressions of pyruvate kinase isoenzyme type M2 (PKM2) and activin A receptor type IC (ACVR 1C) in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) were examined using immunohistochemistry. RESULTS Positive PKM2 and negative ACVR 1C expressions were significantly associated with lymph node metastasis, invasion and TNM stage of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that either elevated PKM2 or loss of ACVR 1C expression significantly correlated with shorter average survival times in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive PKM2 expression and loss of ACVR 1C expression were poor prognosis biomarkers in both SC/ASC and AC patients. CONCLUSIONS Our study suggested that PKM2 overexpression is a marker of metastasis, invasion and poor prognosis of GBC. ACVR 1C is a tumor suppressor, and lowered ACVR 1C expression is an important marker for the metastasis, invasion, and prognosis of GBC.
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MESH Headings
- Activin Receptors, Type I/metabolism
- Activin Receptors, Type I/physiology
- Adenocarcinoma/diagnosis
- Adenocarcinoma/metabolism
- Adenocarcinoma/mortality
- Adenocarcinoma/pathology
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/metabolism
- Carcinoma, Adenosquamous/diagnosis
- Carcinoma, Adenosquamous/metabolism
- Carcinoma, Adenosquamous/mortality
- Carcinoma, Adenosquamous/pathology
- Carcinoma, Squamous Cell/diagnosis
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/pathology
- Carrier Proteins/metabolism
- Carrier Proteins/physiology
- Female
- Gallbladder Neoplasms/diagnosis
- Gallbladder Neoplasms/metabolism
- Gallbladder Neoplasms/mortality
- Gallbladder Neoplasms/pathology
- Humans
- Male
- Membrane Proteins/metabolism
- Membrane Proteins/physiology
- Middle Aged
- Neoplasm Metastasis
- Prognosis
- Thyroid Hormones/metabolism
- Thyroid Hormones/physiology
- Thyroid Hormone-Binding Proteins
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Affiliation(s)
- J Li
- Department of Surgery, Central South University, Changsha, 410011, Hunan, People's Republic of China
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40
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Ganapathy-Kanniappan S, Geschwind JFH. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer 2013; 12:152. [PMID: 24298908 PMCID: PMC4223729 DOI: 10.1186/1476-4598-12-152] [Citation(s) in RCA: 925] [Impact Index Per Article: 77.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 11/21/2013] [Indexed: 12/15/2022] Open
Abstract
Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the “hallmarks of cancer”. This metabolic phenotype is characterized by preferential dependence on glycolysis (the process of conversion of glucose into pyruvate followed by lactate production) for energy production in an oxygen-independent manner. Although glycolysis is less efficient than oxidative phosphorylation in the net yield of adenosine triphosphate (ATP), cancer cells adapt to this mathematical disadvantage by increased glucose up-take, which in turn facilitates a higher rate of glycolysis. Apart from providing cellular energy, the metabolic intermediates of glycolysis also play a pivotal role in macromolecular biosynthesis, thus conferring selective advantage to cancer cells under diminished nutrient supply. Accumulating data also indicate that intracellular ATP is a critical determinant of chemoresistance. Under hypoxic conditions where glycolysis remains the predominant energy producing pathway sensitizing cancer cells would require intracellular depletion of ATP by inhibition of glycolysis. Together, the oncogenic regulation of glycolysis and multifaceted roles of glycolytic components underscore the biological significance of tumor glycolysis. Thus targeting glycolysis remains attractive for therapeutic intervention. Several preclinical investigations have indeed demonstrated the effectiveness of this therapeutic approach thereby supporting its scientific rationale. Recent reviews have provided a wealth of information on the biochemical targets of glycolysis and their inhibitors. The objective of this review is to present the most recent research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions in order to explore the potential for therapeutic opportunities. Further, we discuss the translational potential of emerging drug candidates in light of technical advances in treatment modalities such as image-guided targeted delivery of cancer therapeutics.
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Affiliation(s)
- Shanmugasundaram Ganapathy-Kanniappan
- Russell H Morgan Department of Radiology & Radiological Sciences, Division of Interventional Radiology, Johns Hopkins University School of Medicine, 600 N, Wolfe Street, Blalock Building 340, 21287 Baltimore, MD, USA.
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41
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Zhang X, He C, He C, Chen B, Liu Y, Kong M, Wang C, Lin L, Dong Y, Sheng H. Nuclear PKM2 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Pathol Res Pract 2013; 209:510-5. [PMID: 23880164 DOI: 10.1016/j.prp.2013.06.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Revised: 05/24/2013] [Accepted: 06/01/2013] [Indexed: 12/17/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common tumors worldwide, with a high malignant degree and poor prognosis. The present study aims to investigate the relationship between pyruvate kinase M2 (PKM2) expression and the prognosis of patients with ESCC. The expression of PKM2 in 86 cases of esophageal carcinoma tissues was tested using immunohistochemistry. The relationship between PKM2 expression and clinical pathological parameters, and their effects on the prognosis of patients with ESCC were analyzed. The expression levels of PKM2 in both cytoplasm and nucleus of ESCC tissues were significantly higher than those in paracancerous tissues (P=6.73×10(-9) and 4.32×10(-6), respectively). The Kaplan-Meier analysis showed that nuclear PKM2 expression was closely related to the survival of patients with ESCC (P=0.005). Patients with high PKM2 expression in the nucleus had significantly shorter survival times than those with low PKM2 expression in the nucleus (hazard ratio for death, 2.358; 95% confidence interval, 1.156-4.812; P=0.018). No other significant difference was found between PMK2 expression and clinico-pathological features of ESCC patients (all P>0.05). In conclusion, high PKM2 expression in the nucleus is essential in the pathogenic process of ESCC and may be used to predict the prognosis of patients with ESCC.
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Affiliation(s)
- Xuelin Zhang
- Department of Thoracic Surgery, Taizhou Central Hospital, Taizhou, Zhejiang, China
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42
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Bettaieb A, Bakke J, Nagata N, Matsuo K, Xi Y, Liu S, AbouBechara D, Melhem R, Stanhope K, Cummings B, Graham J, Bremer A, Zhang S, Lyssiotis CA, Zhang ZY, Cantley LC, Havel PJ, Haj FG. Protein tyrosine phosphatase 1B regulates pyruvate kinase M2 tyrosine phosphorylation. J Biol Chem 2013; 288:17360-71. [PMID: 23640882 PMCID: PMC3682537 DOI: 10.1074/jbc.m112.441469] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 04/24/2013] [Indexed: 11/06/2022] Open
Abstract
Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and adiposity and is a drug target for the treatment of obesity and diabetes. Here we identify pyruvate kinase M2 (PKM2) as a novel PTP1B substrate in adipocytes. PTP1B deficiency leads to increased PKM2 total tyrosine and Tyr(105) phosphorylation in cultured adipocytes and in vivo. Substrate trapping and mutagenesis studies identify PKM2 Tyr-105 and Tyr-148 as key sites that mediate PTP1B-PKM2 interaction. In addition, in vitro analyses illustrate a direct effect of Tyr-105 phosphorylation on PKM2 activity in adipocytes. Importantly, PTP1B pharmacological inhibition increased PKM2 Tyr-105 phosphorylation and decreased PKM2 activity. Moreover, PKM2 Tyr-105 phosphorylation is regulated nutritionally, decreasing in adipose tissue depots after high-fat feeding. Further, decreased PKM2 Tyr-105 phosphorylation correlates with the development of glucose intolerance and insulin resistance in rodents, non-human primates, and humans. Together, these findings identify PKM2 as a novel substrate of PTP1B and provide new insights into the regulation of adipose PKM2 activity.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Kimber Stanhope
- From the Nutrition Department and
- Department of Molecular Biosciences, University of California Davis, Davis, California 95616
| | - Bethany Cummings
- From the Nutrition Department and
- Department of Molecular Biosciences, University of California Davis, Davis, California 95616
| | - James Graham
- From the Nutrition Department and
- Department of Molecular Biosciences, University of California Davis, Davis, California 95616
| | - Andrew Bremer
- the Department of Pediatrics, Vanderbilt University, Nashville, Tennessee 37232
| | - Sheng Zhang
- the Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, Indiana 46202
| | - Costas A. Lyssiotis
- the Beth Israel Deaconess Medical Center, Department of Medicine, and
- Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, and
| | - Zhong-Yin Zhang
- the Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, Indiana 46202
| | - Lewis C. Cantley
- the Beth Israel Deaconess Medical Center, Department of Medicine, and
- Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, and
| | - Peter J. Havel
- From the Nutrition Department and
- Department of Molecular Biosciences, University of California Davis, Davis, California 95616
| | - Fawaz G. Haj
- From the Nutrition Department and
- the Department of Internal Medicine and
- Comprehensive Cancer Center, University of California Davis, Sacramento, California 95817
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Tamada M, Suematsu M, Saya H. Pyruvate kinase M2: multiple faces for conferring benefits on cancer cells. Clin Cancer Res 2013; 18:5554-61. [PMID: 23071357 DOI: 10.1158/1078-0432.ccr-12-0859] [Citation(s) in RCA: 187] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The M2 splice isoform of pyruvate kinase (PKM2), an enzyme that catalyzes the later step of glycolysis, is a key regulator of aerobic glycolysis (known as the Warburg effect) in cancer cells. Expression and low enzymatic activity of PKM2 confer on cancer cells the glycolytic phenotype, which promotes rapid energy production and flow of glycolytic intermediates into collateral pathways to synthesize nucleic acids, amino acids, and lipids without the accumulation of reactive oxygen species. PKM2 enzymatic activity has also been shown to be negatively regulated by the interaction with CD44 adhesion molecule, which is a cell surface marker for cancer stem cells. In addition to the glycolytic functions, nonglycolytic functions of PKM2 in cancer cells are of particular interest. PKM2 is induced translocation into the nucleus, where it activates transcription of various genes by interacting with and phosphorylating specific nuclear proteins, endowing cancer cells with a survival and growth advantage. Therefore, inhibitors and activators of PKM2 are well underway to evaluate their anticancer effects and suitability for use as novel therapeutic strategies.
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Affiliation(s)
- Mayumi Tamada
- Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan
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Brandi J, Dando I, Palmieri M, Donadelli M, Cecconi D. Comparative proteomic and phosphoproteomic profiling of pancreatic adenocarcinoma cells treated with CB1 or CB2 agonists. Electrophoresis 2013; 34:1359-68. [PMID: 23463621 DOI: 10.1002/elps.201200402] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Revised: 02/07/2013] [Accepted: 02/08/2013] [Indexed: 01/06/2023]
Abstract
The pancreatic adenocarcinoma cell line Panc1 was treated with cannabinoid receptor ligands (arachidonylcyclopropylamide or GW405833) in order to elucidate the molecular mechanism of their anticancer effect. A proteomic approach was used to analyze the protein and phosphoprotein profiles. Western blot and functional data mining were also employed in order to validate results, classify proteins, and explore their potential relationships. We demonstrated that the two cannabinoids act through a widely common mechanism involving up- and down-regulation of proteins related to energetic metabolism and cell growth regulation. Overall, the results reported might contribute to the development of a therapy based on cannabinoids for pancreatic adenocarcinoma.
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Affiliation(s)
- Jessica Brandi
- Proteomics and Mass Spectrometry Laboratory, Department of Biotechnology, University of Verona, Verona, Italy
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45
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Mitterberger MC, Zwerschke W. Mechanisms of Resveratrol-Induced Inhibition of Clonal Expansion and Terminal Adipogenic Differentiation in 3T3-L1 Preadipocytes. ACTA ACUST UNITED AC 2013; 68:1356-76. [DOI: 10.1093/gerona/glt019] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Wu H, Xie J, Pan Q, Wang B, Hu D, Hu X. Anticancer agent shikonin is an incompetent inducer of cancer drug resistance. PLoS One 2013; 8:e52706. [PMID: 23300986 PMCID: PMC3536779 DOI: 10.1371/journal.pone.0052706] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 11/19/2012] [Indexed: 01/17/2023] Open
Abstract
PURPOSE Cancer drug resistance is a major obstacle for the success of chemotherapy. Since most clinical anticancer drugs could induce drug resistance, it is desired to develop candidate drugs that are highly efficacious but incompetent to induce drug resistance. Numerous previous studies have proven that shikonin and its analogs not only are highly tumoricidal but also can bypass drug-transporter and apoptotic defect mediated drug resistance. The purpose of this study is to investigate if or not shikonin is a weak inducer of cancer drug resistance. EXPERIMENTAL DESIGN Different cell lines (K562, MCF-7, and a MDR cell line K562/Adr), after repeatedly treated with shikonin for 18 months, were assayed for drug resistance and gene expression profiling. RESULTS After 18-month treatment, cells only developed a mere 2-fold resistance to shikonin and a marginal resistance to cisplatin and paclitaxel, without cross resistance to shikonin analogs and other anticancer agents. Gene expression profiles demonstrated that cancer cells did strongly respond to shikonin treatment but failed to effectively mobilize drug resistant machineries. Shikonin-induced weak resistance was associated with the up-regulation of βII-tubulin, which physically interacted with shikonin. CONCLUSION Taken together, apart from potent anticancer activity, shikonin and its analogs are weak inducers of cancer drug resistance and can circumvent cancer drug resistance. These merits make shikonin and its analogs potential candidates for cancer therapy with advantages of avoiding induction of drug resistance and bypassing existing drug resistance.
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Affiliation(s)
- Hao Wu
- Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jiansheng Xie
- Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qiangrong Pan
- Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Beibei Wang
- Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Danqing Hu
- Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xun Hu
- Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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Huang HQ, Tang J, Zhou ST, Yi T, Peng HL, Shen GB, Xie N, Huang K, Yang T, Wu JH, Huang CH, Wei YQ, Zhao X. Orlistat, a novel potent antitumor agent for ovarian cancer: proteomic analysis of ovarian cancer cells treated with Orlistat. Int J Oncol 2012; 41:523-32. [PMID: 22581080 DOI: 10.3892/ijo.2012.1465] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 03/19/2012] [Indexed: 11/06/2022] Open
Abstract
Orlistat is an orally administered anti-obesity drug that has shown significant antitumor activity in a variety of tumor cells. To identify the proteins involved in its antitumor activity, we employed a proteomic approach to reveal protein expression changes in the human ovarian cancer cell line SKOV3, following Orlistat treatment. Protein expression profiles were analyzed by 2-dimensional polyacrylamide gel electrophoresis (2-DE) and protein identification was performed on a MALDI-Q-TOF MS/MS instrument. More than 110 differentially expressed proteins were visualized by 2-DE and Coomassie brilliant blue staining. Furthermore, 71 proteins differentially expressed proteins were positively identified via mass spectrometry (MS)/MS analysis. In particular, PKM1/2, a key enzyme involved in tumorigenesis, was found to be significantly downregulated in SKOV3 cells following treatment with Orlistat. Moreover, PKM1/2 was proved to be downregulated in SKOV3 cells by western blot analysis after treatment with Orlistat. Taken together, using proteomic tools, we identified several differentially expressed proteins that underwent Orlistat-induced apoptosis, particularly PKM2. These changes confirmed our hypothesis that Orlistat is a potential inhibitor of ovarian cancer and can be used as a novel adjuvant antitumor agent.
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Affiliation(s)
- Hui-Qiong Huang
- Department of Gynecology and Obstetrics, Sichuan University, Chengdu, Sichuan, People's Republic of China
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Chaneton B, Gottlieb E. Rocking cell metabolism: revised functions of the key glycolytic regulator PKM2 in cancer. Trends Biochem Sci 2012; 37:309-16. [PMID: 22626471 DOI: 10.1016/j.tibs.2012.04.003] [Citation(s) in RCA: 202] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 04/10/2012] [Accepted: 04/19/2012] [Indexed: 01/05/2023]
Abstract
Cancer cell metabolism is exemplified by high glucose consumption and lactate production. Pyruvate kinase (PK), which catalyzes the final step of glycolysis, has emerged as a potential regulator of this metabolic phenotype. The M2 isoform of PK (PKM2) is highly expressed in cancer cells. However, the mechanisms by which PKM2 coordinates high energy requirements with high anabolic activities to support cancer cell proliferation are still not completely understood. Current research has elucidated novel regulatory mechanisms for PKM2, contributing to its important role in cancer. This review summarizes the current understanding and explores future directions in the field, highlighting controversies regarding the activity and specificity of PKM2 in cancer. In light of this knowledge, the potential therapeutic implications and strategies are critically discussed.
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Affiliation(s)
- Barbara Chaneton
- Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow, UK
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Granchi C, Minutolo F. Anticancer agents that counteract tumor glycolysis. ChemMedChem 2012; 7:1318-50. [PMID: 22684868 PMCID: PMC3516916 DOI: 10.1002/cmdc.201200176] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Revised: 05/04/2012] [Indexed: 12/12/2022]
Abstract
Can we consider cancer to be a "metabolic disease"? Tumors are the result of a metabolic selection, forming tissues composed of heterogeneous cells that generally express an overactive metabolism as a common feature. In fact, cancer cells have increased needs for both energy and biosynthetic intermediates to support their growth and invasiveness. However, their high proliferation rate often generates regions that are insufficiently oxygenated. Therefore, their carbohydrate metabolism must rely mostly on a glycolytic process that is uncoupled from oxidative phosphorylation. This metabolic switch, also known as the Warburg effect, constitutes a fundamental adaptation of tumor cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumor glycolysis may constitute an attractive target for cancer therapy. This approach has often raised concerns that antiglycolytic agents may cause serious side effects toward normal cells. The key to selective action against cancer cells can be found in their hyperbolic addiction to glycolysis, which may be exploited to generate new anticancer drugs with minimal toxicity. There is growing evidence to support many glycolytic enzymes and transporters as suitable candidate targets for cancer therapy. Herein we review some of the most relevant antiglycolytic agents that have been investigated thus far for the treatment of cancer.
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Affiliation(s)
- Carlotta Granchi
- Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa (Italy)
| | - Filippo Minutolo
- Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa (Italy)
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50
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Zhou CF, Li XB, Sun H, Zhang B, Han YS, Jiang Y, Zhuang QL, Fang J, Wu GH. Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells. IUBMB Life 2012; 64:775-82. [DOI: 10.1002/iub.1066] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 05/31/2012] [Indexed: 12/27/2022]
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