Subcellular Hsp70 Inhibitors Promote Cancer Cell Death via Different Mechanisms.

Abstract

Mechanisms underlying cancer cell death caused by inhibitors of subcellular Hsp70 proteins have been elucidated. An inhibitor of Hsp70, apoptozole (Az), is mainly translocated into lysosomes of cancer cells where it induces lysosomal membrane permeabilization, thereby promoting lysosome-mediated apoptosis. Additionally, Az impairs autophagy in cancer cells owing to its ability to disrupt the lysosomal function. However, the Az-triphenylphosphonium conjugate, Az-TPP-O3, localizes mainly to mitochondria of cancer cells where it inhibits the mortalin-p53 interaction and induces mitochondrial outer membrane permeabilization, consequently leading to mitochondria-mediated apoptosis. Unlike Az, Az-TPP-O3 does not have an effect on autophagy in cancer cells. Collectively, the findings indicate that inhibitors of lysosomal Hsp70 and mitochondrial mortalin enhance cancer cell death via distinctively different mechanisms. Additionally, the findings arising from this effort demonstrate that studies aimed at determining subcellular locations and functions of small-molecule modulators provide a deeper understanding of their modes of action in cells.

• Authors: Sang-Hyun Park, Kyung-Hwa Baek, Insu Shin, Injae Shin
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 25 Issue 10 Pg. 1242-1254.e8 (10 18 2018) ISSN: 2451-9448 [Electronic] United States
• PMID: 30057298 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzamides
• HSP70 Heat-Shock Proteins
• Imidazoles
• Organophosphorus Compounds
• Small Molecule Libraries
• apoptozole
• mortalin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Benzamides (pharmacology)
• Cell Line, Tumor
• HSP70 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Imidazoles (pharmacology)
• Lysosomes (drug effects, metabolism, pathology)
• Mitochondria (drug effects, metabolism, pathology)
• Neoplasms (drug therapy, metabolism, pathology)
• Organophosphorus Compounds (pharmacology)
• Small Molecule Libraries (pharmacology)