title: Extracellular PKM2 induces cancer proliferation by activating the EGFR signaling pathway.
abstract: Pyruvate kinase is a key enzyme in the glycolytic pathway that converts phosphoenolpyruvate to pyruvate, and the M2 isoform of pyruvate kinase (PKM2) is associated with cancer. PKM2 has been reported to function independently of its pyruvate kinase activity, which is crucial for cancer cell proliferation. Moreover, there is growing evidence indicating that dimeric PKM2 is released from tumor cells into the circulation of cancer patients. However, the role of secreted PKM2 in cancer is not well understood. Here, we found that the phosphorylation level of epidermal growth factor receptor (EGFR) significantly increased upon the exposure of cells to the recombinant PKM2 protein. In addition, secreted PKM2 induces EGFR phosphorylation and activates the EGFR downstream signaling in triple-negative breast cancer cells. In contrast, knocking down PKM2 decreased EGFR phosphorylation. Moreover, expression of R399E mutant PKM2, which has been reported to preferentially form a dimer, enhanced EGFR phosphorylation, cellular transformation, and cell proliferation more strongly than the wild-type PKM2. Thus, our study revealed a novel function of extracellular PKM2 in the promoting cancer cell proliferation through EGFR activation.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA; National Institute of Cancer Research, National Health Research InstitutesTainan, Taiwan.
authors.forename: Ming-Chuan
authors.initials: MC
authors.lastname: Hsu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes Tainan, Taiwan.
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, TX, USA.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, TX, USA.
authors.forename: Seung-Oe
authors.initials: SO
authors.lastname: Lim
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, TX, USA.
authors.forename: Hsin-Wei
authors.initials: HW
authors.lastname: Liao
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes Tainan, Taiwan.
authors.forename: Chia-Hua
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical UniversityTaichung, Taiwan; Department of Biotechnology, Asia UniversityTaichung, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
keywords: EGFR; PKM2; triple-negative breast cancer