Pyruvate kinase M2 affects liver cancer cell behavior through up-regulation of HIF-1α and Bcl-xL in culture

Dong, Tianfu; Yan, Yue; Chai, Hao; Chen, Shenglin; Xiong, Xinkui; Sun, Daoyi; Yu, Yue; Deng, Lei; Cheng, Feng

doi:10.1016/j.biopha.2014.12.010

Cited by 51 publications

(38 citation statements)

References 45 publications

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“…PKM2 has three functions in cancer cells: (1) cytoplasmic PKM2 is a tetramer with high enzyme activity, and takes part in glycolysis to provide increased metabolic intermediates for cancer cell biosynthesis, (2) the dimeric isoform of PKM2 can translocate to nucleus and act as a transcriptional co-activator, thereby facilitating the transcription of genes beneficial to growth, such as GLUTs, HIF-1α, VEGF-A, Bax, Bcl-2, and PCNA. (3) PKM2 can also translocate to the mitochondria under oxidative stress to interact with Bcl-2/ Bcl-xl, causing the inhibition of cancer cell apoptosis [51][52][53]. Based on the critical role of PKM2, Zhang et al reported that silencing PKM2 could re-sensitize Hep3B-SR and LM3-SR cells to Sora [33].…”

Section: Discussionmentioning

confidence: 99%

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Jiao

Dai

Mao

et al. 2020

J Exp Clin Cancer Res

158

127

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Background: Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC. Methods: The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections.Results: Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1α/PPAR-γ/PKM2 axis. Conclusions: Simvastatin can inhibit the HIF-1α/PPAR-γ/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.

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Section: Discussionmentioning

confidence: 99%

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Jiao

Dai

Mao

et al. 2020

J Exp Clin Cancer Res

158

127

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“…A recent study demonstrated that the expression of PKM2 is up-regulated in HCC and is a predictor of survival and recurrence[33]. Dong et al[34] revealed the oncogenic role of PKM2 in HCC proliferation by its regulation of the expression of HIF-1α and Bcl-xL. Another study further observed that PKM2 effects on cell growth depend on a glucose rather than glutaminolysis pathways by using PKM2 knockdown-sensitive HCC cells.…”

Section: Reprogramming Of Glucose Metabolism-related Enzymes and Tranmentioning

confidence: 99%

Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects

Shang

Wang

2016

WJG

107

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Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due to the difficulties in early diagnosis and the high level of tumor invasion, metastasis and recurrence. It is urgent to explore the underlying mechanism of HCC carcinogenesis and progression to find out the specific biomarkers for HCC early diagnosis and the promising target for HCC chemotherapy. Recently, the reprogramming of cancer metabolism has been identified as a hallmark of cancer. The shift from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in HCC meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. Such metabolic reprogramming could be considered as a critical link between the different HCC genotypes and phenotypes. The regulation of metabolic reprogramming in cancer is complex and may occur via genetic mutations and epigenetic modulations including oncogenes, tumor suppressor genes, signaling pathways, noncoding RNAs, and glycolytic enzymes etc. Understanding the regulatory mechanisms of glycolysis in HCC may enrich our knowledge of hepatocellular carcinogenesis and provide important foundations in the search for novel diagnostic biomarkers and promising therapeutic targets for HCC.

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“…10 PKM2 is expressed in tumor cells. 11,12 The signal transduction and activator 3 (STAT3) signaling pathway and its downstream target genes are involved in the regulation of tumor cell apoptosis by promoting tumor cell proliferation and inhibition of apoptosis in two ways to improve the ability of cancer against cytotoxic drugs. 13,14 STAT3 is active in many hematological and solid tumors, including myeloma, lung cancer, prostate cancer, ovarian cancer, GC, and so on.…”

Section: Introductionmentioning

confidence: 99%

Crosstalk of mTOR/PKM2 and STAT3/c‐Myc signaling pathways regulate the energy metabolism and acidic microenvironment of gastric cancer

Gao

Chen

Wei

et al. 2018

J of Cellular Biochemistry

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Cancer cells consume large amounts of glucose to produce lactate, even in the presence of ample oxygen. This phenomenon is called the Warburg effect. c‐Myc is an important member of the Myc gene family and is involved in the development of various tumors. It plays an important role in the regulation of tumor energy metabolism, which can regulate glycolysis to promote the Warburg effect in a tumor. Our study aimed to improve the malignant biological behavior by controlling the energy metabolism of gastric cancer through the mTOR/PKM2 and signal transduction and activator 3 (STAT3)/c‐Myc signaling pathways through a series of in vitro experiments. Human gastric cancer AGS and HGC‐27 cells were treated with PKM2 and c‐Myc lentivirus, and the effects of the knockdown of PKM2 and/or c‐Myc were analyzed on cell proliferation, cell apoptosis, the ability of cell migration, and the growth signaling pathway in vitro. The expressions of PKM2, c‐Myc, LDHA, STAT3, P‐STAT3, GLUT‐1 gene were identified by the quantitative real‐time polymerase chain reaction and Western blot analysis. Lactate and glucose levels were tested by the corresponding kit. Our findings showed that PKM2 and c‐Myc were upregulated in human gastric cancer. Knockdown of c‐Myc in gastric cancer cells suppressed cell proliferation capacity and glycolysis level, and the inhibitory effects on gastric cancer cells upon co‐knockdown of PKM2 and c‐Myc were more obvious compared with knockout of PKM2 or c‐Myc alone. And there was a correlation between the mTOR/PKM2 and the STAT3/c‐Myc signaling pathways. Our results suggested that c‐Myc might be considered a potential therapeutic target for gastric cancer and PKM2 combined with c‐Myc could better inhibit the malignant biological behaviors of gastric cancer.

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Pyruvate kinase M2 affects liver cancer cell behavior through up-regulation of HIF-1α and Bcl-xL in culture

Cited by 51 publications

References 45 publications

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects

Crosstalk of mTOR/PKM2 and STAT3/c‐Myc signaling pathways regulate the energy metabolism and acidic microenvironment of gastric cancer

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