Heat shock proteins, cell survival and drug resistance: the mitochondrial chaperone TRAP1, a potential novel target for ovarian cancer therapy.

Abstract

BACKGROUND:

Protein homeostasis is a highly complex network of molecular interactions governing the health and life span of the organism. Molecular chaperones, mainly heat shock proteins (HSP) and other stress-inducible proteins abundantly expressed in multiple compartments of the cell, are major modulators of protein homeostasis. TRAP1 is a mitochondrial HSP involved in protection against oxidant-induced DNA damage and apoptosis. It was recently described as a component of a mitochondrial pathway selectively up-regulated in tumor cells which antagonizes the proapoptotic activity of cyclophilin D, a mitochondrial permeability transition pore regulator, and is responsible for the maintenance of mitochondrial integrity, thus favoring cell survival. Interestingly, novel TRAP1 antagonists cause sudden collapse of mitochondrial function and selective tumor cell death, suggesting that this pathway may represent a novel molecular target to improve anticancer therapy. Preliminary data suggest that TRAP1 may be a valuable biomarker in ovarian cancers: in fact, TRAP1 levels are significantly higher in cisplatin-resistant ovarian tumors and ovarian carcinoma cell lines.

CONCLUSIONS:

While major advances have been made in understanding the genetics and molecular biology of cancer, given the considerable heterogeneity of ovarian cancer, the introduction of novel targeted therapies and the consequent selection of treatments based on the molecular profile of each tumor may have a major impact on the management of this malignancy and might contribute to building a new era of personalized medicine.

• Authors: Matteo Landriscina, Maria Rosaria Amoroso, Annamaria Piscazzi, Franca Esposito
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 117 Issue 2 Pg. 177-82 (May 2010) ISSN: 1095-6859 [Electronic] United States
• PMID: 19942270 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright (c) 2009 Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers, Tumor
• HSP90 Heat-Shock Proteins
• TRAP1 protein, human

Topics

• Biomarkers, Tumor (metabolism)
• Cell Survival (drug effects)
• Drug Delivery Systems
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Ovarian Neoplasms (drug therapy, metabolism, pathology)