The Chk2-PKM2 Axis Promotes Metabolic Control of Vasculogenic Mimicry Formation in P53-mutated Triple-negative Breast Cancer

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2021 Jul 10

PMID 34244606

Citations 8

Authors

Pei Yu

Xiong Zhu

Jia-le Zhu

Yu-Bao Han

Hao Zhang

Xiang Zhou

Lei Yang

Yuan-Zheng Xia

Chao Zhang

Ling-Yi Kong

Affiliations

Soon will be listed here.

Abstract

Vasculogenic mimicry (VM) formation, which participates in the process of neovascularization, is highly activated in p53-mutated triple-negative breast cancer (TNBC). Here, we show that Chk2 is negatively correlated with VM formation in p53-mutated TNBC. Its activation by DNA-damaging agents such as cisplatin, etoposide, and DPT reduces VM formation. Mechanistically, the Chk2-PKM2 axis plays an important role in the inhibition of VM formation at the level of metabolic regulation. Chk2 promotes the Chk2-PKM2 interaction through the Chk2 SCD (SQ/TQ cluster domain) and the PKM2 C domain. Furthermore, Chk2 promotes the nuclear export of PKM2 by phosphorylating PKM2 at Ser100. P-PKM2 S100 reduces VM formation by decreasing glucose flux, and the PKM2 S100A mutation abolishes the inhibition of glucose flux and VM formation induced by Chk2 activation. Overall, this study proposes a novel strategy of VM suppression through Chk2 induction, which prevents PKM2-mediated glucose flux in p53-mutated TNBC.

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