Subcellular Hsp70 Inhibitors Promote Cancer Cell Death via Different Mechanisms

Sang Hyun Park, Kyung Hwa Baek, Insu Shin, Injae Shin

Research output: Contribution to journalArticle

7 Citations (Scopus)

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. Detailed mechanisms by which inhibitors of lysosomal Hsp70 and mitochondrial mortalin promote cancer cell death are unknown. Park et al. show that while an inhibitor of lysosomal Hsp70 induces apoptosis and inhibits autophagy, an inhibitor of mitochondrial Hsp70 induces apoptosis without affecting autophagy.

Original languageEnglish
Pages (from-to)1242-1254.e8
JournalCell Chemical Biology
Volume25
Issue number10
DOIs
Publication statusPublished - 2018 Oct 18

Fingerprint

Cell death
Cell Death
Cells
Apoptosis
Autophagy
Mitochondria
Neoplasms
Membranes
Lysosomes
Modulators
Mitochondrial Membranes
Molecules
apoptozole
mortalin
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Park, Sang Hyun ; Baek, Kyung Hwa ; Shin, Insu ; Shin, Injae. / Subcellular Hsp70 Inhibitors Promote Cancer Cell Death via Different Mechanisms. In: Cell Chemical Biology. 2018 ; Vol. 25, No. 10. pp. 1242-1254.e8.
@article{f085947d5be6437185300a0be9cc4fcc,
title = "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. Detailed mechanisms by which inhibitors of lysosomal Hsp70 and mitochondrial mortalin promote cancer cell death are unknown. Park et al. show that while an inhibitor of lysosomal Hsp70 induces apoptosis and inhibits autophagy, an inhibitor of mitochondrial Hsp70 induces apoptosis without affecting autophagy.",
author = "Park, {Sang Hyun} and Baek, {Kyung Hwa} and Insu Shin and Injae Shin",
year = "2018",
month = "10",
day = "18",
doi = "10.1016/j.chembiol.2018.06.010",
language = "English",
volume = "25",
pages = "1242--1254.e8",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "10",

}

Subcellular Hsp70 Inhibitors Promote Cancer Cell Death via Different Mechanisms. / Park, Sang Hyun; Baek, Kyung Hwa; Shin, Insu; Shin, Injae.

In: Cell Chemical Biology, Vol. 25, No. 10, 18.10.2018, p. 1242-1254.e8.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Subcellular Hsp70 Inhibitors Promote Cancer Cell Death via Different Mechanisms

AU - Park, Sang Hyun

AU - Baek, Kyung Hwa

AU - Shin, Insu

AU - Shin, Injae

PY - 2018/10/18

Y1 - 2018/10/18

N2 - 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. Detailed mechanisms by which inhibitors of lysosomal Hsp70 and mitochondrial mortalin promote cancer cell death are unknown. Park et al. show that while an inhibitor of lysosomal Hsp70 induces apoptosis and inhibits autophagy, an inhibitor of mitochondrial Hsp70 induces apoptosis without affecting autophagy.

AB - 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. Detailed mechanisms by which inhibitors of lysosomal Hsp70 and mitochondrial mortalin promote cancer cell death are unknown. Park et al. show that while an inhibitor of lysosomal Hsp70 induces apoptosis and inhibits autophagy, an inhibitor of mitochondrial Hsp70 induces apoptosis without affecting autophagy.

UR - http://www.scopus.com/inward/record.url?scp=85054591334&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054591334&partnerID=8YFLogxK

U2 - 10.1016/j.chembiol.2018.06.010

DO - 10.1016/j.chembiol.2018.06.010

M3 - Article

C2 - 30057298

AN - SCOPUS:85054591334

VL - 25

SP - 1242-1254.e8

JO - Cell Chemical Biology

JF - Cell Chemical Biology

SN - 2451-9448

IS - 10

ER -