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Subcellular Hsp70 Inhibitors Promote Cancer Cell Death via Different Mechanisms

Sang-Hyun Park1, Kyung-Hwa Baek1, Insu Shin1

  • 1Center for Biofunctional Molecules, Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea.

Cell Chemical Biology
|July 31, 2018
PubMed

Insights

Cancer cell death mechanisms were clarified using Hsp70 inhibitors. Apoptozole targets lysosomes, while Az-TPP-O3 targets mitochondria, both inducing apoptosis through distinct pathways.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Heat shock proteins (Hsp70) play roles in cancer cell survival.
  • Targeting Hsp70 at different subcellular locations may offer novel cancer therapy strategies.

Purpose of the Study:

  • To elucidate the distinct mechanisms of cancer cell death induced by Hsp70 inhibitors.
  • To investigate the role of subcellular localization in the efficacy of cancer therapeutics.

Main Methods:

  • Utilized apoptozole (Az), an Hsp70 inhibitor, and its conjugate Az-TPP-O3.
  • Examined subcellular localization (lysosomes vs. mitochondria) in cancer cells.
  • Assessed effects on lysosomal and mitochondrial membrane permeabilization and autophagy.

Main Results:

  • Apoptozole (Az) induced lysosomal membrane permeabilization and impaired autophagy.
  • Az-triphenylphosphonium conjugate (Az-TPP-O3) inhibited mortalin-p53 interaction and induced mitochondrial outer membrane permeabilization, without affecting autophagy.
  • Both compounds effectively promoted cancer cell death via distinct apoptotic pathways.

Conclusions:

  • Inhibitors of lysosomal Hsp70 and mitochondrial mortalin induce cancer cell death through different mechanisms.
  • Understanding the subcellular targets and functions of small molecules is crucial for deciphering their mode of action and therapeutic potential.
Keywords:
anticancer activityapoptosis inducerautophagy inhibitormode of actionsmall-molecule inhibitors

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