Selective elimination of pluripotent stem cells by PIKfyve specific inhibitors.

Abstract

Inhibition of PIKfyve phosphoinositide kinase selectively kills autophagy-dependent cancer cells by disrupting lysosome homeostasis. Here, we show that PIKfyve inhibitors can also selectively eliminate pluripotent embryonal carcinoma cells (ECCs), embryonic stem cells, and induced pluripotent stem cells under conditions where differentiated cells remain viable. PIKfyve inhibitors prevented lysosome fission, induced autophagosome accumulation, and reduced cell proliferation in both pluripotent and differentiated cells, but they induced death only in pluripotent cells. The ability of PIKfyve inhibitors to distinguish between pluripotent and differentiated cells was confirmed with xenografts derived from ECCs. Pretreatment of ECCs with the PIKfyve specific inhibitor WX8 suppressed their ability to form teratocarcinomas in mice, and intraperitoneal injections of WX8 into mice harboring teratocarcinoma xenografts selectively eliminated pluripotent cells. Differentiated cells continued to proliferate, but at a reduced rate. These results provide a proof of principle that PIKfyve specific inhibitors can selectively eliminate pluripotent stem cells in vivo as well as in vitro.

• Authors: Arup R Chakraborty, Alex Vassilev, Sushil K Jaiswal, Constandina E O'Connell, John F Ahrens, Barbara S Mallon, Martin F Pera, Melvin L DePamphilis
• Journal: Stem cell reports (Stem Cell Reports) Vol. 17 Issue 2 Pg. 397-412 (02 08 2022) ISSN: 2213-6711 [Electronic] United States
• PMID: 35063131 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• Enzyme Inhibitors
• Hydrazines
• hydrazine
• DNA
• PIKFYVE protein, human

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy
• Cell Line
• Cell Survival (drug effects)
• DNA (metabolism)
• Embryonic Stem Cells (cytology, metabolism)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• G1 Phase
• Humans
• Hydrazines (chemistry, pharmacology, therapeutic use)
• Mice
• Mice, Nude
• Phosphatidylinositol 3-Kinases (chemistry, metabolism)
• Pluripotent Stem Cells (cytology, drug effects, metabolism)
• Teratocarcinoma (drug therapy, pathology)
• Transplantation, Heterologous