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Exosome Release from Tumor Cells Promoted by PKM2 Phosphorylation of Synaptosome-Associated Protein 23

In a study published online on January 9, 2017 in Nature Communications, a research team led by Dr. Ke Zen and Dr. Chen-Yu Zhang from Nanjing University in China reports that pyruvate kinase type M2 (PKM2) promotes tumor cell exosome release through phosphorylating synaptosome-associated protein 23 (SNAP-23). The open-access article is titled “Pyruvate Kinase Type M2 Promotes Tumour Cell Exosome Release Via Phosphorylating Synaptosome-Associated Protein 23.” As a mechanism to communicate with the microenvironment, tumor cells actively release large numbers 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, the 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. Specifically, the researchers 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 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, not only in switching tumor cell metabolism from oxidative phosphorylation to aerobic glycolysis, but also in 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 immune cells under inflammatory stimuli.

[Press release] [Nature Communications article]