Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

Guo, Wenjing; Zhang, Zhishuai; Li, Guihuan; Lai, Xiaorong; Gu, Ruonan; Xu, Wei; Chen, Hua; Xing, Zhe; Chen, Liping; Qian, Jiabi; Xu, Shiyuan; Zeng, Fanning; Deng, Fan

doi:10.3389/fonc.2020.544288

Cited by 35 publications

(27 citation statements)

References 48 publications

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“…Consistent with this finding, PKM2 expression in liver cancer cells affects the flux of glucose metabolism [37]. Another potential mechanism is also suggested by findings in prostate cancer, where PKM2 promotes metastasis by modulating the extracellular-regulated protein kinase-cyclooxygenase pathway [38].…”

Section: Discussionsupporting

confidence: 67%

Cinnamic acid inhibits cell viability, invasion, and glycolysis in primary endometrial stromal cells by suppressing NF-κB-induced transcription of PKM2

et al. 2021

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Background: Endometriosis is a painful disorder characterized by the growth of endometrial tissue outside the uterine cavity. Here, we investigated the effects of the cinnamic acid isolated from the Chinese medicinal plant Cinnamomum cassia Presl on primary endometrial stromal cells. Methods: Immunohistochemistry was used to examine protein expression and cell purity. Quantitative RT-PCR was conducted to assess mRNA expression, and Western blot was performed to determine protein level. Cell viability was assessed using cell counting kit-8 (CCK-8) assay. Glycolysis and mitochondrial function were evaluated by measuring the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) of cells, respectively. Lastly, plasmid transfection and inhibitor treatment were used for overexpression and inhibition studies. Results: Cinnamic acid inhibited cell viability and cell invasion, as well as decreased ECAR and OCR, in primary endometrial stromal cells. Cinnamic acid suppressed the effects of PKM2 overexpression, and inhibition of PKM2 using Compound 3k mimicked the effects of cinnamic acid. Treatment with Compound 3k and cinnamic acid did not lead to additive effects, but rather displayed effects similar to those of Compound 3k alone, suggesting that cinnamic acid elicits its effects on primary endometrial stromal cells by targeting PKM2. Conclusions: Our study identified cinnamic acid as a novel compound from Cinnamomum cassia Presl that displays potent effects on primary endometrial stromal cell viability, invasion, and glycolysis, suggesting its potential use for endometriosis treatment.

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Section: Discussionsupporting

confidence: 67%

Cinnamic acid inhibits cell viability, invasion, and glycolysis in primary endometrial stromal cells by suppressing NF-κB-induced transcription of PKM2

et al. 2021

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“…Prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase-2(COX-2), a crucial enzyme in the process of arachidonic acid conversion to prostaglandins and other eicosanoids, was reported to promote malignant metastasis in colorectal tumor cells (Fenwick et al, 2003). In addition, Guo et al (2020) demonstrated that PKM2 upregulates COX-2 expression, leading to epithelialmesenchymal transition (EMT) and metastasis of PCa, by promoting the phosphorylation of ERK1/2. More studies on the role of COX-2 in the regulation of PCa metastasis are required.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of a PPP1R12A-Related Five-Gene Signature Associated With Metabolism to Predict the Prognosis of Patients With Prostate Cancer

et al. 2021

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BackgroundProstate cancer (PCa) is the most common malignant male neoplasm in the American male population. Our prior studies have demonstrated that protein phosphatase 1 regulatory subunit 12A (PPP1R12A) could be an efficient prognostic factor in patients with PCa, promoting further investigation. The present study attempted to construct a gene signature based on PPP1R12A and metabolism-related genes to predict the prognosis of PCa patients.MethodsThe mRNA expression profiles of 499 tumor and 52 normal tissues were extracted from The Cancer Genome Atlas (TCGA) database. We selected differentially expressed PPP1R12A-related genes among these mRNAs. Tandem affinity purification-mass spectrometry was used to identify the proteins that directly interact with PPP1R12A. Gene set enrichment analysis (GSEA) was used to extract metabolism-related genes. Univariate Cox regression analysis and a random survival forest algorithm were used to confirm optimal genes to build a prognostic risk model.ResultsWe identified a five-gene signature (PPP1R12A, PTGS2, GGCT, AOX1, and NT5E) that was associated with PPP1R12A and metabolism in PCa, which effectively predicted disease-free survival (DFS) and biochemical relapse-free survival (BRFS). Moreover, the signature was validated by two internal datasets from TCGA and one external dataset from the Gene Expression Omnibus (GEO).ConclusionThe five-gene signature is an effective potential factor to predict the prognosis of PCa, classifying PCa patients into high- and low-risk groups, which might provide potential novel treatment strategies for these patients.

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“…Based on the data herein and overexpression of various glycolytic proteins including ALDOA and PKM2 in cancer, suggest that patients with tumors overexpressing DNA-PK and/or ALDOA/PKM2 may benefit from combination of DNA-PK and ALDOA/PKM2 inhibitors. In PCa targeting PKM2 via siRNA leads to decrease proliferation and metastasis in PCa [50,51], thus combination with DNA-PKi may show greater anti-cancerous activity. Moreover, since upregulated glycolysis is a hallmark of cancer [32], patients may benefit from combination therapy of single agent activity in vitro but its interrogation was halted in phase I/II clinical trials for treatment of solid tumors, including hormone refractory PCa, due to limited efficacy on inhibiting tumor growth and high toxicities [52].…”

Section: Combination Of Dna-pk and Glycolysis Inhibitor Decreases Proliferation In Crpcmentioning

confidence: 99%

A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer

Dylgjeri

Kothari

Shafi

et al. 2022

Clinical Cancer Research

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Purpose: DNA-dependent kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer (PCa), and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. While DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes.Experimental Design: Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacological and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE).Results: Key findings reveal: i) the first-in-field DNA-PK protein-protein interactome; ii) numerous DNA-PK novel partners involved in glycolysis, iii) DNA-PK interacts with, phosphorylates (in vitro) and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2, iv) DNA-PK drives synthesis of glucose-derived pyruvate and lactate, v) DNA-PK regulates glycolysis in vitro, in vivo and ex vivo, and vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive antiproliferative effects in aggressive disease.Conclusions: Findings herein unveil novel DNA-PK partners, substrates, and function in PCa. The role of DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production Research.

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Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

Cited by 35 publications

References 48 publications

Cinnamic acid inhibits cell viability, invasion, and glycolysis in primary endometrial stromal cells by suppressing NF-κB-induced transcription of PKM2

Cinnamic acid inhibits cell viability, invasion, and glycolysis in primary endometrial stromal cells by suppressing NF-κB-induced transcription of PKM2

Identification and Validation of a PPP1R12A-Related Five-Gene Signature Associated With Metabolism to Predict the Prognosis of Patients With Prostate Cancer

A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer

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