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Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis
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Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis
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Journal Article
Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis
2018
Overview
A
bstract
Enhanced glycolysis in cancer cells has been linked to cell protection from DNA damaging signals, although the mechanism is largely unknown. The 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) catalyzes the generation of fructose-2,6-bisphosphate, a potent allosteric stimulator of glycolysis. Intriguingly, among the four members of PFKFB family, PFKFB3 is uniquely localized in the nucleus, although the reason remains unclear. Here we show that chemotherapeutic agent cisplatin promotes glycolysis, which is suppressed by
PFKFB3
deletion. Mechanistically, cisplatin induces PFKFB3 acetylation at lysine 472 (K472), which impairs activity of the nuclear localization signal (NLS) and accumulates PFKFB3 in the cytoplasm. Cytoplasmic accumulation of PFKFB3 facilitates its phosphorylation by AMPK, leading to PFKFB3 activation and enhanced glycolysis. Inhibition of PFKFB3 sensitizes tumor to cisplatin treatment in a xenograft model. Our findings reveal a mechanism for cells to stimulate glycolysis to protect from DNA damage and potentially suggest a therapeutic strategy to sensitize tumor cells to genotoxic agents by targeting PFKFB3.
Enhanced glycolysis in cancer cells has been associated with protection from DNA damage. Here the authors show that DNA damaging signals induce acetylation of PFKFB3 at lysine K472 and promote its cytosolic accumulation, which enhances glycolysis, resulting in protection from cisplatin-induced cell death.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 82/58
/ Adenylate Kinase - drug effects
/ Adenylate Kinase - metabolism
/ Antineoplastic Agents - pharmacology
/ Cancer
/ Damage
/ DNA
/ Enzymes
/ Fructose
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Lysine
/ Nuclear Localization Signals - drug effects
/ Nuclear Localization Signals - metabolism
/ Nuclei
/ Phosphofructokinase-2 - drug effects
/ Phosphofructokinase-2 - metabolism
/ Phosphorylation - drug effects
/ Proteins
/ Science
