期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2002486118
关键词
lipid kinase; chemical biology; p53; pip4k; synthetic lethality
资金
- Yale University
- NIH [GM112778, GM138722, GM122473]
- YCMD pilot grant
Most human cancer cells have mutations in the p53 tumor suppressor gene. Inhibition of PI5P4K alpha and beta disrupts cell energy balance and is selectively toxic towards p53-null tumor cells, indicating the potential for development of novel diabetes and cancer drugs.
Most human cancer cells harbor loss-of-function mutations in the p53 tumor suppressor gene. Genetic experiments have shown that phosphatidylinositol 5-phosphate 4-kinase alpha and beta (PI5P4K alpha and PI5P4K beta) are essential for the development of late-onset tumors in mice with germline p53 deletion, but the mechanism underlying this acquired dependence remains unclear. PI5P4K has been previously implicated in metabolic regulation. Here, we show that inhibition of PI5P4K alpha/beta kinase activity by a potent and selective small-molecule probe disrupts cell energy homeostasis, causing AMPK activation and mTORC1 inhibition in a variety of cell types. Feedback through the S6K/insulin receptor substrate (IRS) loop contributes to insulin hypersensitivity and enhanced PI3K signaling in terminally differentiated myotubes. Most significantly, the energy stress induced by PI5P4K alpha beta inhibition is selectively toxic toward p53-null tumor cells. The chemical probe, and the structural basis for its exquisite specificity, provide a promising platform for further development, which may lead to a novel class of diabetes and cancer drugs.
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