A family of PIKFYVE inhibitors with therapeutic potential against autophagy-dependent cancer cells disrupt multiple events in lysosome homeostasis

Autophagy
Gaurav SharmaMelvin L DePamphilis

Abstract

High-throughput screening identified 5 chemical analogs (termed the WX8-family) that disrupted 3 events in lysosome homeostasis: (1) lysosome fission via tubulation without preventing homotypic lysosome fusion; (2) trafficking of molecules into lysosomes without altering lysosomal acidity, and (3) heterotypic fusion between lysosomes and autophagosomes. Remarkably, these compounds did not prevent homotypic fusion between lysosomes, despite the fact that homotypic fusion required some of the same machinery essential for heterotypic fusion. These effects varied 400-fold among WX8-family members, were time and concentration dependent, reversible, and resulted primarily from their ability to bind specifically to the PIKFYVE phosphoinositide kinase. The ability of the WX8-family to prevent lysosomes from participating in macroautophagy/autophagy suggested they have therapeutic potential in treating autophagy-dependent diseases. In fact, the most potent family member (WX8) was 100-times more lethal to 'autophagy-addicted' melanoma A375 cells than the lysosomal inhibitors hydroxychloroquine and chloroquine. In contrast, cells that were insensitive to hydroxychloroquine and chloroquine were also insensitive to WX8. Therefore, the WX8-f...Continue Reading

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Citations

Nov 7, 2019·The FEBS Journal·Lavinia PalamiucBrooke M Emerling
May 20, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yao-Cheng LiGeoffrey M Wahl
Oct 23, 2019·Cancers·Marta Pérez-HernándezVanessa Soto-Cerrato
May 14, 2020·Autophagy·Laura Devis-JaureguiDavid Llobet-Navàs
Aug 9, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yuan-Lin KangTom Kirchhausen
Aug 23, 2019·Cancer Discovery·Ravi K AmaravadiJayanta Debnath
Jan 24, 2021·Journal of Cell Science·Timothy MarshJayanta Debnath
Jan 26, 2021·Frontiers in Cell and Developmental Biology·Amra Saric, Spencer A Freeman
Apr 9, 2021·The Journal of Biological Chemistry·Alberto Carpinteiro SoaresLouis De Muynck
Oct 29, 2020·ACS Infectious Diseases·Anil Mathew TharappelHongmin Li
May 11, 2021·Journal of Medicinal Chemistry·Javier García-CárcelesAna Martínez
Mar 5, 2020·Cell Chemical Biology·Sindhu Carmen SivakumarenNathanael S Gray
Jul 5, 2021·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Noor A HusseinAmit K Tiwari
Aug 26, 2021·Journal of Cell Science·Timothy MarshJayanta Debnath
Aug 24, 2021·Frontiers in Pharmacology·Olivier Preynat-SeauveKarl-Heinz Krause
Sep 1, 2021·Leukemia·Sreoshee RafiqMagali Humbert
Sep 24, 2021·Journal of Proteome Research·Shirley QiuMarceline Côté
Nov 24, 2021·PloS One·Golam T SaffiRoberto J Botelho

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Methods Mentioned

BETA
light microscopy
electron microscopy
Fluorescence
confocal microscopy
PCR
phase contrast microscopy
xenografts
transfection

Software Mentioned

ImageJ
DiscoverX KINOMEscan

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