PKM2 in carcinogenesis and oncotherapy

He, Xia; Du, Suya; Lei, Tiantian; Li, Xiang; Liu, Yilong; Wang, Hailian; Tong, Rongsheng; Wang, Yi

doi:10.18632/oncotarget.22529

Cited by 48 publications

(45 citation statements)

References 98 publications

(128 reference statements)

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“…Additionally, the majority of FFPE specimens of this study had cytoplasmic PKM2 staining, but in few specimens nuclear localization of PKM2 was revealed as well. This finding confirms the pleiotropic activity of PKM2 that includes not only its enzyme role but also its role as a co-activator transcription factor [37,38]. More experiments are needed in order to detect the exact interactions of PKM2 transcription co-factor and the genes whereby the latter alters their transcription.…”

Section: Discussionsupporting

confidence: 71%

Correlation of PKM2 and CD44 Protein Expression with Poor Prognosis in Platinum-Treated Epithelial Ovarian Cancer: A Retrospective Study

Papadaki

Manolakou

Lagoudaki

et al. 2020

Cancers

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CD44, a surface marker for cancer stem cells, interacts with PKM2, a key regulator of aerobic glycolysis, and enhances the glycolytic phenotype of cancer cells leading to antioxidant protection and macromolecules’ synthesis. To clarify the clinical importance of this “cross-talk” as a mechanism of drug resistance, we assessed the expression both of PKM2 and of CD44 in cancer cells of patients with epithelial ovarian cancer (EOC) treated with platinum-based treatment. One hundred and seventy-one patients with EOC were assessed for PKM2mRNA expression and PKM2 and CD44 proteins detection. Associations with progression-free survival (PFS) and overall survival (OS) were assessed with Kaplan–Meier and adjusted Cox regression models. PKM2mRNA and protein as well as CD44 protein were detectable in the majority of patients. Positive correlation between PKM2 and CD44 protein expression was observed (Spearman rho = 0.2, p = 0.015). When we used the median to group patients into high versus low expression, high PKM2mRNA and protein levels were significantly associated with lower progression-free survival (PFS; p = 0.003 and p = 0.002, respectively) and shorter overall survival (OS; p ≤ 0.001 and p = 0.001, respectively). However, high CD44 protein expression was significantly correlated only with shorter OS (p = 0.004). Moreover, patients with both high PKM2 and CD44 protein levels experienced shorter PFS and OS (p = 0.007 and p = 0.003, respectively) compared to patients with low expression of both proteins. Finally, higher PKM2mRNA and protein expression as well as CD44 protein expression (HR: 2.16; HR: 1.82; HR: 1.01, respectively) were independent prognostic factors for decreased median OS (mOS), whereas only PKM2 protein expression (HR: 1.95) was an independent prognostic factor for decreased median PFS (mPFS). In conclusion, PKM2 expression is a negative prognostic factor in EOC patients, but the interaction between CD44 and PKM2 that may be implicated in EOC platinum-resistance needs further investigation.

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Section: Discussionsupporting

confidence: 71%

Correlation of PKM2 and CD44 Protein Expression with Poor Prognosis in Platinum-Treated Epithelial Ovarian Cancer: A Retrospective Study

Papadaki

Manolakou

Lagoudaki

et al. 2020

Cancers

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“…PKM2 is necessary for the shift in cellular metabolism to aerobic glycolysis, which promotes tumorigenesis, cell division, apoptosis, and metastasis. 22 , 23 Several types of tumor cells have been shown to express the embryonic M2 isoform of pyruvate kinase exclusively. 24 , 25 …”

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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“…Grafting of spinal-cord-derived neural progenitor cells sustains the embryonic transcriptional profile in CST motor neurons enabling the regeneration of corticospinal axons (36). Aerobic glycolysis or Warburg effect in cancer cells is a reprogrammed metabolism resulting from increased glucose uptake and lactate production in the presence of oxygen (37,38). Expression of embryonic isoform of pyruvate kinase PKM2 is required for aerobic glycolysis providing the advantage for tumor growth (37,38).…”

Section: Discussionmentioning

confidence: 99%

“…Aerobic glycolysis or Warburg effect in cancer cells is a reprogrammed metabolism resulting from increased glucose uptake and lactate production in the presence of oxygen (37,38). Expression of embryonic isoform of pyruvate kinase PKM2 is required for aerobic glycolysis providing the advantage for tumor growth (37,38). Reversion of pyruvate kinase to adult isoform PKM1 decreases lactate production and increases oxygen consumption resulting in tumor growth reduction (37,38).…”

Section: Discussionmentioning

confidence: 99%

“…Expression of embryonic isoform of pyruvate kinase PKM2 is required for aerobic glycolysis providing the advantage for tumor growth (37,38). Reversion of pyruvate kinase to adult isoform PKM1 decreases lactate production and increases oxygen consumption resulting in tumor growth reduction (37,38). In the present study, we showed that nuclear Our finding of aberrant MBNL2-regulated RNA processing in cultured neurons caused by NMDAR-activated calpain was consistent with that in brains of individuals with DM1 and MBNL2-knockout animals, which suggests a neuron-specific regulatory role for MBNL2.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Neurodegeneration induces a developmental RNA processing program by calpain-mediated MBNL2 degradation

Wang

Lin

et al. 2020

Preprint

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The Muscleblind-like (MBNL) protein family plays an important role in regulating developmental RNA processing transition. Loss of MBNL2 function has been implicated in the neurodegeneration of myotonic dystrophy type 1 (DM1). However, the causal mechanism of neurodegeneration-induced MBNL2 loss of function remains elusive. Here, we show that neurodegenerative conditions including NMDAR-mediated excitotoxicity and dysregulated calcium homeostasis triggered nuclear translocation of calpain-2 resulting in MBNL2 degradation and reversion of MBNL2-regulated RNA processing to developmental patterns. The developmental stage featured nucleus-enriched distribution of calpain-2 and low expression of MBNL2. Increased MBNL2 expression during development is required for promoting developmental RNA processing transition and neuronal maturation. Knockdown of calpain-2 expression inhibited neurodegeneration-induced MBNL2 reduction and dysregulated RNA processing. Neurodegenerative disease mouse models including DM1 and Alzheimer’s disease showed nuclear translocation of calpain-2 associated with MBNL2 degradation and reversion of MBNL2-regulated RNA processing to the developmental pattern. Our results identify a novel regulatory mechanism for MBNL2 downregulation and suggest that reduced MBNL2 expression accompanied by the re-induction of a developmental RNA processing program may be a common feature of neurodegeneration.

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PKM2 in carcinogenesis and oncotherapy

Cited by 48 publications

References 98 publications

Correlation of PKM2 and CD44 Protein Expression with Poor Prognosis in Platinum-Treated Epithelial Ovarian Cancer: A Retrospective Study

Correlation of PKM2 and CD44 Protein Expression with Poor Prognosis in Platinum-Treated Epithelial Ovarian Cancer: A Retrospective Study

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

Neurodegeneration induces a developmental RNA processing program by calpain-mediated MBNL2 degradation

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