PKM2, a Central Point of Regulation in Cancer Metabolism

Wong, Nicholas; Melo, Jason De; Tang, Damu

doi:10.1155/2013/242513

Cited by 200 publications

(177 citation statements)

References 106 publications

(171 reference statements)

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“…Moreover, rescuing p53 in LFS-derived stromal cells led to inhibition of HIF-1␣ levels. PKM2 is a key mediator of the Warburg effect, the phenomenon by which proliferating cells alter their mode of energy production from oxidative phosphorylation to aerobic glycolysis, and its expression is increased in cancer cells (35,36). Although the metabolic function of PKM2 is well established, our findings support a role for this protein as a regulator of gene expression via direct interactions with HIF-1␣.…”

Section: Discussionmentioning

confidence: 51%

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Subbaramaiah

Brown

Zahid

et al. 2016

Journal of Biological Chemistry

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Li-Fraumeni syndrome (LFS) patients harbor germ line mutations in the TP53 gene and are at increased risk of hormone receptor-positive breast cancers. Recently, elevated levels of aromatase, the rate-limiting enzyme for estrogen biosynthesis, were found in the breast tissue of LFS patients. Although p53 down-regulates aromatase expression, the underlying mechanisms are incompletely understood. In the present study, we found that LFS stromal cells expressed higher levels of Hsp90 ATPase activity and aromatase compared with wild-type stromal cells. Inhibition of Hsp90 ATPase suppressed aromatase expression. Silencing Aha1 (activator of Hsp90 ATPase 1), a cochaperone of Hsp90 required for its ATPase activity, led to both inhibition of Hsp90 ATPase activity and reduced aromatase expression. In comparison with wild-type stromal cells, increased levels of the Hsp90 client proteins, HIF-1␣, and PKM2 were found in LFS stromal cells. A complex comprised of HIF-1␣ and PKM2 was recruited to the aromatase promoter II in LFS stromal cells. Silencing either HIF-1␣ or PKM2 suppressed aromatase expression in LFS stromal cells. CP-31398, a p53 rescue compound, suppressed levels of Aha1, Hsp90 ATPase activity, levels of PKM2 and HIF-1␣, and aromatase expression in LFS stromal cells. Consistent with these in vitro findings, levels of Hsp90 ATPase activity, Aha1, HIF-1␣, PKM2, and aromatase were increased in the mammary glands of p53 null versus wild-type mice. PKM2 and HIF-1␣ were shown to co-localize in the nucleus of stromal cells of LFS breast tissue. Taken together, our results show that the Aha1-Hsp90-PKM2/ HIF-1␣ axis mediates the induction of aromatase in LFS.Estrogen is an important mediator in the development and progression of breast cancer. Cytochrome P450 aromatase, a product of the CYP19A1 gene, catalyzes the synthesis of estrogens from androgens (1). In postmenopausal women, the adipose tissue becomes the main site of estrogen biosynthesis, and particularly, the breast adipose tissue is considered an important source of estrogens that drive the growth of hormone-dependent breast cancers. Consequently, it is important to elucidate the mechanisms that regulate the transcription of the CYP19A1 gene. The expression of aromatase is tightly regulated, with transcription being under the control of several distinct tissue-selective promoters (2-4). In normal breast adipose tissue, aromatase is expressed at low levels under the control of promoter I.4, whereas in obesity and cancer, the coordinated activation of the proximal promoters I.3 and promoter II (PII) 3 causes a significant increase in aromatase expression (3-5). The proximal promoters I.3 and PII are located close to each other, activated by stimulation of the cAMP 3 PKA 3 cAMP response element-binding protein (CREB) pathway (6, 7), and aided by many other regulators including CREB-regulated transcription co-activator 2 (CRTC2), p300, and hypoxia-inducible factor-1␣ (HIF-1␣) (8 -11).Several cytokines and tumor promoters, including prostaglandin E 2 , tumor necrosis ...

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Section: Discussionmentioning

confidence: 51%

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Subbaramaiah

Brown

Zahid

et al. 2016

Journal of Biological Chemistry

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“…Interestingly, decreased expression of c-myc and cyclin D1 were also observed in present study ( Figure 6F). This reason may be that different dosages and treating time of have different effects on the proliferation of some cell lines, PKM2 is a key glycolytic enzyme that regulates the Warburg effect and is necessary for tumor growth (Wong et al, 2013). Recent studies indicated that nuclear PKM2 could activate gene transcription and cell proliferation in human glioblastoma, prostate cancer and breast cancer cells (Gao et al, 2012;Lee et al, 2008;Luo et al, 2011a;Luo et al, 2011b).…”

Section: Discussionmentioning

confidence: 99%

PKM2 Regulates Hepatocellular Carcinoma Cell Epithelial-mesenchymal Transition and Migration upon EGFR Activation

Fan

Shen²,

Li³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Pyruvate kinase isozyme type M2 (PKM2) was first found in hepatocellular carcinoma (HCC), and its expression has been thought to correlate with prognosis. A large number of studies have demonstrated that epithelial-mesenchymal transition (EMT) is a crucial event in hepatocellular carcinoma (HCC) and associated metastasis, resulting in enhanced malignancy of HCC. However, the roles of PKM2 in HCC EMT and metastasis remain largely unknown. The present study aimed to determine the effects of PKM2 in EGF-induced HCC EMT and elucidate the molecular mechanisms in vitro. Our results showed that EGF promoted EMT in HCC cell lines as evidenced by altered morphology, expression of EMT-associated markers, and enhanced invasion capacity. Furthermore, the present study also revealed that nuclear translocation of PKM2, which is regulated by the ERK pathway, regulated β-catenin-TCF/LEF-1 transcriptional activity and associated EMT in HCC cell lines. These discoveries provide evidence of novel roles of PKM2 in the progression of HCC and potential therapeutic target for advanced cases.

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“…6d). Thus, the ratio of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] ]CO 2 to [6-14 ]CO 2 was decreased (Fig. 6e).…”

Section: Pim2 Promotes Pkm2-dependent Glycolysis and Reduces Mitochonmentioning

confidence: 99%

“…Because PKM2 has a lower enzymatic activity compared with PKM1, it will channel more glycolytic intermediates into building blocks, such as nucleic acids, amino acids, and lipids, to support cancer cell proliferation. The enzymatic activity of PKM2 is under the control of metabolic intermediates, oncogenes, and growth factors (6). Growing evidence indicates that oncogenes reprogram glycolysis, impacting the tumor aggressive phenotype via regulating PKM2 (7).…”

mentioning

confidence: 99%

Proviral Insertion in Murine Lymphomas 2 (PIM2) Oncogene Phosphorylates Pyruvate Kinase M2 (PKM2) and Promotes Glycolysis in Cancer Cells

Zhao

Huang

et al. 2013

Journal of Biological Chemistry

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Background:The protein-serine/threonine kinase PIM2 regulates glycolysis, but the mechanism is not fully elucidated. Results: PIM2 interacts with PKM2 and phosphorylates PKM2 on the Thr-454 residue. Conclusion: This phosphorylation of PKM2 increases glycolysis and proliferation in cancer cells. Significance: PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer, highlighting PIM2 as a potential therapeutic target.

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PKM2, a Central Point of Regulation in Cancer Metabolism

Cited by 200 publications

References 106 publications

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells

PKM2 Regulates Hepatocellular Carcinoma Cell Epithelial-mesenchymal Transition and Migration upon EGFR Activation

Proviral Insertion in Murine Lymphomas 2 (PIM2) Oncogene Phosphorylates Pyruvate Kinase M2 (PKM2) and Promotes Glycolysis in Cancer Cells

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