Pyruvate kinase M2 is a poor prognostic marker of and a therapeutic target in ovarian cancer

Chao, Tai-Kuang; Huang, Tien Shuo; Liao, Yu Ping; Huang, Rui; Su, Po Hsuan; Shen, Hueng Yuan; Lai, Hung Cheng; Wang, Yu Chi

doi:10.1371/journal.pone.0182166

Cited by 43 publications

(27 citation statements)

References 30 publications

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“… 29 Chao et al evaluated PKM2 expression in ovarian cancer, reporting that patients with higher PKM2 levels correlated significantly with malignancy groups ( P <0.001) and pathogenesis models ( P <0.001) and had poor PFS ( P =0.01) compared with patients exhibiting lower PKM2 levels. 30 …”

Section: Discussionmentioning

confidence: 99%

Expression of pyruvate kinase M2 in human bladder cancer and its correlation with clinical parameters and prognosis

Huang¹,

Huang²,

Bai³

et al. 2018

OTT

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BackgroundPyruvate kinase M2 (PKM2) is a key regulator of the Warburg effect and has critical functions in glycolysis, contributing to the Warburg effect, tumor growth, angiogenesis, cell division, metastasis, and apoptosis. The high expression of PKM2 in various solid tumors renders it a potential biomarker of tumorigenesis and tumor invasion, but the expression and role of PKM2 in bladder cancer have not been studied extensively.Patients and methodsWestern blot and immunohistochemistry (IHC) were used to measure the expression of PKM2, and quantitative real-time polymerase chain reaction (PCR) was performed to determine PKM2 mRNA levels. The relationships between PKM2 expression and clinicopathological parameters and prognosis were analyzed using the Kaplan–Meier plots and a Cox proportional hazards regression model.ResultsCompared with paired adjacent normal bladder tissues, PKM2 mRNA and protein levels were found to be higher in urothelial carcinoma of the bladder (UCB) samples by real-time PCR and Western blot. By IHC, high expression of PKM2 was seen in 117 of 215 UCBs (54.4%) and in eight of 90 adjacent normal bladder tissues (8.9%). The expression of PKM2 was significantly associated with grade, stage, and lymph node status (P<0.001). In the univariate survival analysis, a significant association between PKM2 expression and shorter patient survival was observed (P<0.001). In different subsets of UCB patients, we found that PKM2 expression was a prognostic factor in patients with G2 (P=0.009), G3 (P<0.001), pTa/pTis (P=0.006), pT1, pT2–4, and pN− disease (P<0.001). Importantly, PKM2 expression (P=0.003), with tumor histological grade (P<0.001), pT (P<0.001), and pN status (P=0.005), was a significant independent prognostic parameter in the multivariate analysis.ConclusionPKM2 protein and mRNA are upregulated in UCBs and may serve as molecular markers for a poor prognosis in patients with UCB.

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Section: Discussionmentioning

confidence: 99%

Expression of pyruvate kinase M2 in human bladder cancer and its correlation with clinical parameters and prognosis

Huang¹,

Huang²,

Bai³

et al. 2018

OTT

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“…PKM2 catalyzes the conversion of phosphoenolpyruvate to pyruvate and regulates the flux of acetyl coA available to enter the tricarboxylic aid cycle. Elevated expression of PKM2 correlates with decreased progression free survival in HGSOC although overall survival is not affected [ 37 ]. Hexokinase II is also upregulated in HGSOC [ 38 , 39 ].…”

Section: Oxphos As Target For Hgsoc Therapymentioning

confidence: 99%

Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer

Nayak

Kapur

Barroilhet

et al. 2018

Cancers

111

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Aerobic glycolysis is an important metabolic adaptation of cancer cells. There is growing evidence that oxidative phosphorylation is also an active metabolic pathway in many tumors, including in high grade serous ovarian cancer. Metastasized ovarian tumors use fatty acids for their energy needs. There is also evidence of ovarian cancer stem cells privileging oxidative phosphorylation (OXPHOS) for their metabolic needs. Metformin and thiazolidinediones such as rosiglitazone restrict tumor growth by inhibiting specific steps in the mitochondrial electron transport chain. These observations suggest that strategies to interfere with oxidative phosphorylation should be considered for the treatment of ovarian tumors. Here, we review the literature that supports this hypothesis and describe potential agents and critical control points in the oxidative phosphorylation pathway that can be targeted using small molecule agents. In this review, we also discuss potential barriers that can reduce the efficacy of the inhibitors of oxidative phosphorylation.

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“…Depletion of PKM2 in a breast cancer mouse xenograft model showed a reversal of the Warburg effect and inhibits tumor growth [47]. High expression of PKM2 is found in malignant OVCA, suggesting its late stage detection role of poor prognosis [48]. The association of PKM2 with tumorigenesis depends on the type of cancer, as the suppression of PKM2 did not show anti-tumor activity in breast and colon cancer, but did in leukemia [49, 50].…”

Section: The Role Of Glycolytic Metabolism In Chemoresistancementioning

confidence: 99%

Tumor metabolism regulating chemosensitivity in ovarian cancer

et al. 2018

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Elevated metabolism is a key hallmark of multiple cancers, serving to fulfill high anabolic demands. Ovarian cancer (OVCA) is the fifth leading cause of cancer deaths in women with a high mortality rate (45%). Chemoresistance is a major hurdle for OVCA treatment. Although substantial evidence suggests that metabolic reprogramming contributes to anti-apoptosis and the metastasis of multiple cancers, the link between tumor metabolism and chemoresistance in OVCA remains unknown. While clinical trials targeting metabolic reprogramming alone have been met with limited success, the synergistic effect of inhibiting tumor-specific metabolism with traditional chemotherapy warrants further examination, particularly in OVCA. This review summarizes the role of key glycolytic enzymes and other metabolic synthesis pathways in the progression of cancer and chemoresistance in OVCA. Within this context, mitochondrial dynamics (fission, fusion and cristae structure) are addressed regarding their roles in controlling metabolism and apoptosis, closely associated with chemosensitivity. The roles of multiple key oncogenes (Akt, HIF-1α) and tumor suppressors (p53, PTEN) in metabolic regulation are also described. Next, this review summarizes recent research of metabolism and future direction. Finally, we examine clinical drugs and inhibitors to target glycolytic metabolism, as well as the rationale for such strategies as potential therapeutics to overcome chemoresistant OVCA.

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Pyruvate kinase M2 is a poor prognostic marker of and a therapeutic target in ovarian cancer

Cited by 43 publications

References 30 publications

Expression of pyruvate kinase M2 in human bladder cancer and its correlation with clinical parameters and prognosis

Expression of pyruvate kinase M2 in human bladder cancer and its correlation with clinical parameters and prognosis

Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer

Tumor metabolism regulating chemosensitivity in ovarian cancer

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