In a study newly published in Nature Communications, A research team led by Dr. Ke Zen and Chen-Yu Zhang from Nanjing University reports that pyruvate kinase type M2 promotes tumor cell exosome release through phosphorylating synaptosome-associated protein 23.
As a mechanism to communicate with the microenvironment, tumor cells actively release large amount of microvesicles (MVs) particularly exosomes. These tumor-released MVs, which are abundant in the body fluids of patients with cancer, play a critical role in promoting tumor growth and progression. The mechanism underlying the active exocytosis of exosomes by tumor cells, however, remains incompletely understood. It has been reported that cellular exocytosis activity is increased during tumorigenesis, but the molecular basis to switch on the exocytosis process in tumor cells has not been identified.
In the present study, Nanjing University team showed that PKM2, an enzyme involved in the tumor cell's reliance on aerobic glycolysis (Warburg effect), plays a critical role in promoting the release of exosomes from the tumor cell. In specific, they identify SNAP-23, which controls the dock and release of secretory granules or exosome-containing multivesicular bodies (MVBs), is a substrate of PKM2 in tumor cells. During exocytosis, phosphorylated PKM2 is recruited to secretory granules or MVBs near cell's membranes where it associates with SNAP-23 and phosphorylates SNAP-23 at Ser95, leading to upregulation of exocytosis in tumor cells. This study demonstrates for the first time that PKM2 plays an essential role in not only switching tumor cell metabolism from oxidative phosphorylation to aerobic glycolysis, but also promoting tumor cell exocytosis via directly phosphorylating SNAP-23. Given that Warburg effect switched on by PKM2 is also an important metabolism mechanism for many non-tumor cells, such as immune cells, the PKM2-mediated secretion may also play a significant role in modulating the secretion or degranulation process in these cells under inflammatory stimuli.
The researchers of this project include Yao Wei, Dong Wang, Fangfang Jin, Mingzhen Li, Chaoyun Pan, Dihan Zhu, Limin Li, Chen-Yu Zhang and Ke Zen from State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University Advanced Institute for Life Sciences (NAILS), Nanjing University School of life sciences (163 Xianlin Road, Nanjing, Jiangsu, 210046), and collaborators Dr. Gang Hu from Nanjing University of Traditional Chinese Medicine (Nanjing, China), and Drs. Yuan Liu, Zhen Bian and Lei Shi from Georgia State University (Atlanta, GA, USA). This work was supported by grants the National Basic Research Program of China (973 Program) (No. 2012CB517603 and 2014CB542300).