Pharmacological inhibition of PI5P4Kα/β disrupts cell energy metabolism and selectively kills p53-null tumor cells

Abstract

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 α and β (PI5P4Kα and PI5P4Kβ) 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 PI5P4Kα/β 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 PI5P4Kαβ 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.

Expanding role of PI5P4Ks in cancer: A promising druggable target

“…Most recently, a noncovalent dual PI5P4Ka/b inhibitor, CC260, was identified using a high-throughput screen among 5759 small molecules. CC260 treatment was shown to affect AKT phosphorylation and impair cellular energetics as demonstrated by changes in AMPK activation, mTOR inhibition, and decreased mitochondrial ATP production [60]. CC260 treatment increased the sensitivity of cancer cells to nutrient stress and was also able to selectively kill p53 mutant breast cancer cells [60], confirming several published data from our laboratory and others.…”

“…In fact, efforts have been made to identify and characterize pan inhibitors [33,34] as well as isoform specific inhibitors of PI5P4Ks [75,76], and over the years, there have been reports of more potent and selective small molecule inhibitors [60,[77][78][79], strengthening the evidence for efficient druggability of the PI5P4Ks. Recently in an attempt to identify drugs that are selectively lethal to cancer cells but not to normal cells, a novel compound, a131, was identified and interestingly, the group discovered that the target of the a131 compound is indeed the PI5P4Ks and it selectively regulated the cell cycle entry of Ras-activated cancer cells resulting in their death through mitotic catastrophe, while causing reversible growth arrest in normal cells [77].…”

Crucial Players for Inter-Organelle Communication: PI5P4Ks and Their Lipid Product PI-4,5-P2 Come to the Surface

“…All things considered, in the recent past, PI5P4Ks and their product PI-4,5-P 2 have risen from insignificance to being without a doubt one of the key metabolic sensors and regulators within the cell as well as pivotal players for interorganelle communication necessary for cell survival. With drugs being developed against these kinases (Davis et al, 2013;Clarke et al, 2015;Al-Ramahi et al, 2017;Kitagawa et al, 2017;Manz et al, 2020;Sivakumaren et al, 2020;Chen et al, 2021), targeting them in the near future in various diseases is looking brighter.…”

PIP4K2B is a mechanosensor and induces heterochromatin-driven nuclear softening through UHRF1

“…Due to the increasing interest on the role of PIP4K signalling in cancer, several inhibitors have been developed. We decided to exploit recently synthesized compounds named A-131 and THZ-P1_2 to understand if pharmacological inhibition of these lipid kinases could recapitulate the depletion of PIP4K2B by sh_RNAi (51, 52). We then treated hTERT_RPE1 cells for 24 hours with both these compounds, and we found that, as well as for the knock-down, inhibition of PIP4K led to decreased NE tension and chromatin decompaction (Figure 6A and 6B).…”

“…During the last years, the rising interest in these enzymes led to the synthesis of different inhibitors targeting this family of phosphotransferases. Here, we took advantage of two compounds, named A131 and THZ-P1_2 (51, 52), in order to understand if direct inhibition of the kinase activity of PIP4K could recapitulate the phenotypes appeared upon PIP4K2B silencing. Interestingly, both the compounds altered cell mechanics, finally impacting on cell capacity to migrate, similarly to cells depleted for PIP4K2B.…”