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

Wenjing Guo,Ruonan Gu,Zhishuai Zhang,Liping Chen,Fangyin Zeng,Fan Deng,Jiabi Qian,Xiaoju Lai,Wanfu Xu,Hua Chen,Shiyuan Xu,Guihuan Li,Zhe Xing

doi:10.3389/fonc.2020.544288

Wenjing Guo, Ruonan Gu + Show 11 more

Open Access

https://doi.org/10.3389/fonc.2020.544288

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Abstract

Pyruvate kinase M2 (PKM2) is a key enzyme of glycolysis, which is highly expressed in many tumor cells, and has emerged as an important player in tumor progression and metastasis. However, the functional roles of PKM2 in tumor metastasis remain elusive. Here we showed that PKM2 promoted prostate cancer metastasis via extracellular-regulated protein kinase (ERK)–cyclooxygenase (COX-2) signaling. Based on public databases, we found that PKM2 expression was upregulated in prostate cancer and positively associated with tumor metastasis. Further analysis showed that PKM2 promoted prostate cancer cell migration/invasion and epithelial–mesenchymal transition (EMT) through upregulation of COX-2. Mechanistically, PKM2 interacted with ERK1/2 and regulated its phosphorylation, leading to phosphorylation of transcription factor c-Jun, downstream of ERK1/2, to activate COX-2 transcription by IP and ChIP assay, while inhibition of COX-2 significantly reversed the promotion effect of PKM2 on tumor metastasis in vivo. Taken together, our results suggest that a novel of PKM2–ERK1/2–c-Jun–COX-2 axis is a potential target in controlling prostate cancer metastasis.

Highlights

Prostate cancer (PCa) is one of the most commonly diagnosed cancers and the third leading cause of cancer death in men around the world, in developed countries [1, 2]
Pyruvate kinase M2 (PKM2) interacted with ERK1/2 and regulated its phosphorylation, leading to phosphorylation of transcription factor c-Jun, downstream of ERK1/2, to activate COX-2 transcription by IP and ChIP assay, while inhibition of COX-2 significantly reversed the promotion effect of PKM2 on tumor metastasis in vivo
We further addressed the high expression of PKM2 in prostate cancer, contributing to COX-2-mediated epithelial–mesenchymal transition (EMT) and tumor metastasis by ERK1/2 signaling in vivo and in vitro

Summary

Introduction

Prostate cancer (PCa) is one of the most commonly diagnosed cancers and the third leading cause of cancer death in men around the world, in developed countries [1, 2]. The development of effective therapy for PCa metastasis had contributed to improve the survival, the metastatic disease is still incurable and lethal [3]. Cancer metastasis is a complex series of events, including migration of cancer cells from their primary tumor, survival in circulation, attachment to the metastatic site, and proliferation as Abbreviations: PKM2, pyruvate kinase M2; COX-2, cyclooxygenase-2; ERK, extracellular-regulated protein kinase; EMT, epithelial–mesenchymal transition; PCa, prostate cancer; ADT, androgen deprivation therapy; ECM, extracellular matrix; MMP, matrix metalloproteinase proteins; MAPK, mitogen-activated protein kinase; AP-1, activator protein 1. COX-2 is highly expressed and correlated with angiogenesis, the contribution of COX-2 in the regulation of prostate cancer metastasis remains unclear [8]

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