Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Oncology in South China, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2018 May 1;78(9):2248-2261. doi: 10.1158/0008-5472.CAN-17-2726. Epub 2018 Feb 12.
The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the -loss-driven mammary tumor mouse model accelerates tumor formation. Because oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas nonphosphorylated PKM2 is nononcogenic. Indeed, PKM2 was phosphorylated at tyrosine 105 (Y105) and formed oncogenic dimers in MDA-MB-231 breast cancer cells, whereas PKM2 was largely unphosphorylated and formed nontumorigenic tetramers in nontransformed MCF10A cells. PKM2 knockdown did not affect MCF10A cell growth but significantly decreased proliferation of MDA-MB-231 breast cancer cells with tyrosine kinase activation. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introduction of the PKM2-Y105D phosphomimetic mutant into MCF10A cells induced colony formation and the CD44/CD24 cancer stem-like cell population by increasing Yes-associated protein (YAP) nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted nuclear localization of YAP and enhanced the cancer stem-like cell population. Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem-like cells, impeding PKM2 tumor-promoting function. Taken together, phosphorylation of PKM2-Y105 by activated kinases exerts oncogenic functions in part via activation of YAP downstream signaling to increase cancer stem-like cell properties. These findings reveal PKM2 promotes tumorigenesis by inducing cancer stem-like cell properties and clarify the paradox of PKM2's dichotomous functions in tumor progression. .
丙酮酸激酶 M2 同工型（PKM2）在肿瘤进展中的作用一直存在争议。先前的研究表明，PKM2 促进异种移植模型中的肿瘤生长；然而，在 -loss 驱动的乳腺肿瘤小鼠模型中耗尽 PKM2 会加速肿瘤形成。由于致癌激酶在肿瘤中经常被激活，并且 PKM2 的磷酸化促进肿瘤生长，我们假设肿瘤细胞中激活的激酶对 PKM2 的磷酸化赋予了 PKM2 的致癌功能，而非磷酸化的 PKM2 是非致癌的。事实上，PKM2 在酪氨酸 105（Y105）处发生磷酸化，并在 MDA-MB-231 乳腺癌细胞中形成致癌二聚体，而 PKM2 主要未磷酸化并在非转化的 MCF10A 细胞中形成非致瘤四聚体。PKM2 敲低不影响 MCF10A 细胞的生长，但显著降低了酪氨酸激酶激活的 MDA-MB-231 乳腺癌细胞的增殖。在我们的酪氨酸激酶筛选中，鉴定出多种在不同癌症类型中经常被激活的激酶可磷酸化 PKM2-Y105。将 PKM2-Y105D 磷酸模拟突变体引入 MCF10A 细胞可通过增加 Yes 相关蛋白（YAP）核定位诱导集落形成和 CD44/CD24 癌症干细胞样细胞群。ErbB2 强烈诱导 PKM2-Y105 磷酸化，增强 YAP 的核定位并增强癌症干细胞样细胞群。用 ErbB2 激酶抑制剂 lapatinib 处理可降低 PKM2-Y105 磷酸化和癌症干细胞样细胞，从而阻碍 PKM2 的肿瘤促进功能。总之，激活的激酶对 PKM2-Y105 的磷酸化通过激活 YAP 下游信号来发挥致癌功能，从而增加癌症干细胞样细胞的特性。这些发现表明 PKM2 通过诱导癌症干细胞样细胞特性来促进肿瘤发生，并阐明了 PKM2 在肿瘤进展中的双重功能的悖论。
