Hsu Ming-Chuan, Hung Wen-Chun, Yamaguchi Hirohito, Lim Seung-Oe, Liao Hsin-Wei, Tsai Chia-Hua, Hung Mien-Chie
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.
National Institute of Cancer Research, National Health Research Institutes Tainan, Taiwan.
Am J Cancer Res. 2016 Feb 15;6(3):628-38. eCollection 2016.
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.
丙酮酸激酶是糖酵解途径中的关键酶，可将磷酸烯醇丙酮酸转化为丙酮酸，丙酮酸激酶的M2亚型（PKM2）与癌症相关。据报道，PKM2的功能独立于其丙酮酸激酶活性，而该活性对癌细胞增殖至关重要。此外，越来越多的证据表明，二聚体PKM2从肿瘤细胞释放到癌症患者的循环中。然而，分泌型PKM2在癌症中的作用尚未得到充分了解。在此，我们发现细胞暴露于重组PKM2蛋白后，表皮生长因子受体（EGFR）的磷酸化水平显著增加。此外，分泌型PKM2可诱导EGFR磷酸化并激活三阴性乳腺癌细胞中的EGFR下游信号传导。相反，敲低PKM2可降低EGFR磷酸化。此外，据报道优先形成二聚体的R399E突变型PKM2的表达比野生型PKM2更强烈地增强了EGFR磷酸化、细胞转化和细胞增殖。因此，我们的研究揭示了细胞外PKM2通过激活EGFR促进癌细胞增殖的新功能。
