Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells

Markus D. Siegelin, Takehiko Dohi, Christopher M. Raskett, Gregory M. Orlowski, Christine M. Powers, Candace A. Gilbert, Alonzo H. Ross, Janet Plescia, Dario C. Altieri

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Fine tuning of the protein folding environment in subcellular organelles, such as mitochondria, is important for adaptive homeostasis and may participate in human diseases, but the regulators of this process are still largely elusive. Here, we have shown that selective targeting of heat shock protein-90 (Hsp90) chaperones in mitochondria of human tumor cells triggered compensatory autophagy and an organelle unfolded protein response (UPR) centered on upregulation of CCAAT enhancer binding protein (C/EBP) transcription factors. In turn, this transcriptional UPR repressed NF-κB-dependent gene expression, enhanced tumor cell apoptosis initiated by death receptor ligation, and inhibited intracranial glioblastoma growth in mice without detectable toxicity. These data reveal what we believe to be a novel role of Hsp90 chaperones in the regulation of the protein-folding environment in mitochondria of tumor cells. Disabling this general adaptive pathway could potentially be used in treatment of genetically heterogeneous human tumors.

Original languageEnglish (US)
Pages (from-to)1349-1360
Number of pages12
JournalJournal of Clinical Investigation
Volume121
Issue number4
DOIs
StatePublished - Apr 1 2011

Fingerprint

Unfolded Protein Response
Mitochondrial Proteins
HSP90 Heat-Shock Proteins
Mitochondria
Protein Folding
Organelles
Neoplasms
CCAAT-Enhancer-Binding Proteins
Death Domain Receptors
Autophagy
Therapeutics
Glioblastoma
Ligation
Homeostasis
Transcription Factors
Up-Regulation
Apoptosis
Gene Expression
Growth

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Siegelin, M. D., Dohi, T., Raskett, C. M., Orlowski, G. M., Powers, C. M., Gilbert, C. A., ... Altieri, D. C. (2011). Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. Journal of Clinical Investigation, 121(4), 1349-1360. https://doi.org/10.1172/JCI44855
Siegelin, Markus D. ; Dohi, Takehiko ; Raskett, Christopher M. ; Orlowski, Gregory M. ; Powers, Christine M. ; Gilbert, Candace A. ; Ross, Alonzo H. ; Plescia, Janet ; Altieri, Dario C. / Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 4. pp. 1349-1360.
@article{92bdb2745cda481b81bbc0e013a7bae9,
title = "Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells",
abstract = "Fine tuning of the protein folding environment in subcellular organelles, such as mitochondria, is important for adaptive homeostasis and may participate in human diseases, but the regulators of this process are still largely elusive. Here, we have shown that selective targeting of heat shock protein-90 (Hsp90) chaperones in mitochondria of human tumor cells triggered compensatory autophagy and an organelle unfolded protein response (UPR) centered on upregulation of CCAAT enhancer binding protein (C/EBP) transcription factors. In turn, this transcriptional UPR repressed NF-κB-dependent gene expression, enhanced tumor cell apoptosis initiated by death receptor ligation, and inhibited intracranial glioblastoma growth in mice without detectable toxicity. These data reveal what we believe to be a novel role of Hsp90 chaperones in the regulation of the protein-folding environment in mitochondria of tumor cells. Disabling this general adaptive pathway could potentially be used in treatment of genetically heterogeneous human tumors.",
author = "Siegelin, {Markus D.} and Takehiko Dohi and Raskett, {Christopher M.} and Orlowski, {Gregory M.} and Powers, {Christine M.} and Gilbert, {Candace A.} and Ross, {Alonzo H.} and Janet Plescia and Altieri, {Dario C.}",
year = "2011",
month = "4",
day = "1",
doi = "10.1172/JCI44855",
language = "English (US)",
volume = "121",
pages = "1349--1360",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "4",

}

Siegelin, MD, Dohi, T, Raskett, CM, Orlowski, GM, Powers, CM, Gilbert, CA, Ross, AH, Plescia, J & Altieri, DC 2011, 'Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells', Journal of Clinical Investigation, vol. 121, no. 4, pp. 1349-1360. https://doi.org/10.1172/JCI44855

Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. / Siegelin, Markus D.; Dohi, Takehiko; Raskett, Christopher M.; Orlowski, Gregory M.; Powers, Christine M.; Gilbert, Candace A.; Ross, Alonzo H.; Plescia, Janet; Altieri, Dario C.

In: Journal of Clinical Investigation, Vol. 121, No. 4, 01.04.2011, p. 1349-1360.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells

AU - Siegelin, Markus D.

AU - Dohi, Takehiko

AU - Raskett, Christopher M.

AU - Orlowski, Gregory M.

AU - Powers, Christine M.

AU - Gilbert, Candace A.

AU - Ross, Alonzo H.

AU - Plescia, Janet

AU - Altieri, Dario C.

PY - 2011/4/1

Y1 - 2011/4/1

N2 - Fine tuning of the protein folding environment in subcellular organelles, such as mitochondria, is important for adaptive homeostasis and may participate in human diseases, but the regulators of this process are still largely elusive. Here, we have shown that selective targeting of heat shock protein-90 (Hsp90) chaperones in mitochondria of human tumor cells triggered compensatory autophagy and an organelle unfolded protein response (UPR) centered on upregulation of CCAAT enhancer binding protein (C/EBP) transcription factors. In turn, this transcriptional UPR repressed NF-κB-dependent gene expression, enhanced tumor cell apoptosis initiated by death receptor ligation, and inhibited intracranial glioblastoma growth in mice without detectable toxicity. These data reveal what we believe to be a novel role of Hsp90 chaperones in the regulation of the protein-folding environment in mitochondria of tumor cells. Disabling this general adaptive pathway could potentially be used in treatment of genetically heterogeneous human tumors.

AB - Fine tuning of the protein folding environment in subcellular organelles, such as mitochondria, is important for adaptive homeostasis and may participate in human diseases, but the regulators of this process are still largely elusive. Here, we have shown that selective targeting of heat shock protein-90 (Hsp90) chaperones in mitochondria of human tumor cells triggered compensatory autophagy and an organelle unfolded protein response (UPR) centered on upregulation of CCAAT enhancer binding protein (C/EBP) transcription factors. In turn, this transcriptional UPR repressed NF-κB-dependent gene expression, enhanced tumor cell apoptosis initiated by death receptor ligation, and inhibited intracranial glioblastoma growth in mice without detectable toxicity. These data reveal what we believe to be a novel role of Hsp90 chaperones in the regulation of the protein-folding environment in mitochondria of tumor cells. Disabling this general adaptive pathway could potentially be used in treatment of genetically heterogeneous human tumors.

UR - http://www.scopus.com/inward/record.url?scp=79953317434&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953317434&partnerID=8YFLogxK

U2 - 10.1172/JCI44855

DO - 10.1172/JCI44855

M3 - Article

C2 - 21364280

AN - SCOPUS:79953317434

VL - 121

SP - 1349

EP - 1360

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -