Necroptosis pathway blockage attenuates PFKFB3 inhibitor-induced cell viability loss and genome instability in colorectal cancer cells

xlomafota13 shared this article with you from Inoreader Necroptosis pathway blockage attenuates PFKFB3 inhibitor-induced cell viability loss and genome instability in colorectal cancer cells Via American Journal of Cancer Research Am J Cancer Res. 2021 May 15;11(5):2062-2080. eCollection 2021. ABSTRACT Cancer cells prone to utilize aerobic glycolysis other than oxidative phosphorylation to sustain its continuous cell activity in the stress microenvironment. Meanwhile, cancer cells generally suffer from genome instability, and both radiotherapy and chemotherapy may arouse DNA strand break, a common phenotype of genome instability. Glycolytic enzyme PFKFB3 (6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3), plays essential roles in variety physiology and pathology processes, and generally maintain high level in cancer cells. Although this protein has been reported to involve in genome instability, its role remains unclear and controversial. Here, we showed that PFK-15, a PFKFB3 inhibitor, obviously induced apoptosis, cell viability loss, and inhibited cell proliferation/migration. Besides, PFK-15 was also found to induce necroptosis, as it not only u p-regulated the phosphorylated RIP1, RIP3 and MLKL, but also enhanced the interaction between RIP3 and RIP1/MLKL, all of which are characterization of necroptosis induction. Both genetically and pharmacologically deprivation of necroptosis attenuated the cytotoxic effect of PFK-15. Besides, PFK-15 increased the γ-H2AX level and micronuclei formation, markers for genome instability, and inhibition of necroptosis attenuated these phenotypes. Collectively, the presented data demonstrated that PFK-15 induced genome instability and necroptosis, and deprivation of necroptosis attenuated cytotoxicity and genotoxicity of PFK-15 in colorectal cancer cells, thereby revealing a more intimate relationship among PFKFB3, necroptosis and genome instability. PMID:34094669 | PMC:PMC8167677 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.