Méndez-Lucas Andrés, Li Xiaolei, Hu Junjie, Che Li, Song Xinhua, Jia Jiaoyuan, Wang Jingxiao, Xie Chencheng, Driscoll Paul C, Tschaharganeh Darjus F, Calvisi Diego F, Yuneva Mariia, Chen Xin
The Francis Crick Institute, London, United Kingdom.
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California.
Cancer Res. 2017 Aug 15;77(16):4355-4364. doi: 10.1158/0008-5472.CAN-17-0498. Epub 2017 Jun 19.
Different pyruvate kinase isoforms are expressed in a tissue-specific manner, with pyruvate kinase M2 (PKM2) suggested to be the predominant isoform in proliferating cells and cancer cells. Because of differential regulation of enzymatic activities, PKM2, but not PKM1, has been thought to favor cell proliferation. However, the role of PKM2 in tumorigenesis has been recently challenged. Here we report that increased glucose catabolism through glycolysis and increased pyruvate kinase activity in c-MYC-driven liver tumors are associated with increased expression of both PKM1 and PKM2 isoforms and decreased expression of the liver-specific isoform of pyruvate kinase, PKL. Depletion of PKM2 at the time of c-MYC overexpression in murine livers did not affect c-MYC-induced tumorigenesis and resulted in liver tumor formation with decreased pyruvate kinase activity and decreased catabolism of glucose into alanine and the Krebs cycle. An increased PKM1/PKM2 ratio by ectopic PKM1 expression further decreased glucose flux into serine biosynthesis and increased flux into lactate and the Krebs cycle, resulting in reduced total levels of serine. However, these changes also did not affect c-MYC-induced liver tumor development. These results suggest that increased expression of PKM2 is not required to support c-MYC-induced tumorigenesis in the liver and that various PKM1/PKM2 ratios and pyruvate kinase activities can sustain glucose catabolism required for this process. .
不同的丙酮酸激酶同工型以组织特异性方式表达，丙酮酸激酶M2（PKM2）被认为是增殖细胞和癌细胞中的主要同工型。由于酶活性的差异调节，人们认为PKM2而非PKM1有利于细胞增殖。然而，PKM2在肿瘤发生中的作用最近受到了挑战。我们在此报告，在c-MYC驱动的肝肿瘤中，通过糖酵解增加的葡萄糖分解代谢和增加的丙酮酸激酶活性与PKM1和PKM2同工型的表达增加以及肝脏特异性丙酮酸激酶同工型PKL的表达降低有关。在小鼠肝脏中c-MYC过表达时PKM2的缺失并不影响c-MYC诱导的肿瘤发生，并导致肝肿瘤形成，同时丙酮酸激酶活性降低，葡萄糖向丙氨酸和三羧酸循环的分解代谢减少。通过异位表达PKM1增加PKM1/PKM2比值进一步降低了葡萄糖进入丝氨酸生物合成的通量，并增加了进入乳酸和三羧酸循环的通量，导致丝氨酸总水平降低。然而，这些变化也不影响c-MYC诱导的肝肿瘤发展。这些结果表明，增加PKM2的表达并非支持肝脏中c-MYC诱导的肿瘤发生所必需，并且各种PKM1/PKM2比值和丙酮酸激酶活性可以维持该过程所需的葡萄糖分解代谢。
