Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC; Genomics Research Center, Academia Sinica, Taipei, Taiwan, ROC.
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
Cancer Lett. 2018 May 1;421:28-40. doi: 10.1016/j.canlet.2018.01.075. Epub 2018 Feb 22.
Cancer cells encounter metabolic stresses such as hypoxia and nutrient limitations because they grow and divide more quickly than their normal counterparts. In response to glucose restriction, we found that nuclear translocation of the glycolic enzyme, pyruvate kinase M2 (PKM2), helped cancer cells survive under the metabolic stress. Restriction of glucose stimulated AMPK activation and resulted in co-translocation of AMPK and PKM2 through Ran-mediated nuclear transport. Nuclear PKM2 subsequently bound to Oct4 and promoted the expression of cancer stemness-related genes, which might enrich the cancer stem cell population under the metabolic stress. Nuclear PKM2 was also capable of promoting cancer metastasis in an orthotopic xenograft model. In summary, we found that cytosolic AMPK helped PKM2 carry out its nonmetabolic functions in the nucleus under glucose restriction and that nuclear PKM2 promoted cancer stemness and metastasis. These findings suggested a potential new targeting pathway for cancer therapy in the future.
癌细胞会遇到代谢应激，如缺氧和营养限制，因为它们的生长和分裂速度比正常细胞快。我们发现，在葡萄糖限制的情况下，糖酵解酶丙酮酸激酶 M2（PKM2）的核转位有助于癌细胞在代谢应激下存活。葡萄糖的限制刺激 AMPK 的激活，并导致 AMPK 和 PKM2 通过 Ran 介导的核转运共转位。核 PKM2 随后与 Oct4 结合，并促进与癌症干细胞相关的基因表达，这可能会在代谢应激下丰富癌症干细胞群体。核 PKM2 还能够在原位异种移植模型中促进癌症转移。总之，我们发现细胞溶质 AMPK 有助于在葡萄糖限制下 PKM2 在核内执行其非代谢功能，并且核 PKM2 促进了癌症干细胞特性和转移。这些发现为未来的癌症治疗提供了一个潜在的新靶点途径。
