Targeting heat shock proteins in cancer.

INSERM U866, 7, Boulevard Jeanne d'Arc, 21033 Dijon, France; University of Burgundy, Esplanade Erasme, 21078 Dijon, France.
Cancer letters (Impact Factor: 5.02). 11/2010; DOI: 10.1016/j.canlet.2010.10.014
Source: PubMed

ABSTRACT Heat shock proteins (HSPs) HSP27, HSP70 and HSP90 are powerful chaperones. Their expression is induced in response to a wide variety of physiological and environmental insults including anti-cancer chemotherapy, thus allowing the cell to survive to lethal conditions. Different functions of HSPs have been described to account for their cytoprotective function, including their role as molecular chaperones as they play a central role in the correct folding of misfolded proteins, but also their anti-apoptotic properties. HSPs are often overexpressed in cancer cells and this constitutive expression is necessary for cancer cells' survival. HSPs may have oncogene-like functions and likewise mediate "non-oncogene addiction" of stressed tumor cells that must adapt to a hostile microenvironment, thereby becoming dependent for their survival on HSPs. HSP-targeting drugs have therefore emerged as potential anti-cancer agents. This review describes the different molecules and approaches being used or proposed in cancer therapy based on the in inhibition of HSP90, HSP70 and HSP27.

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    ABSTRACT: Metabolic rates of cancer cells are faster compared to normal cells. This faster rate yield aberrant protein folding and cause loss of protein function. Therefore, cancer cells need more Heat Shock Proteins (HSPs) for proper substrate protein folding on oncogenic pathways. Pseudogenes regulate tumor suppressors and oncogenes, and pseudogenes are deregulated in cancer progression. Further, alterations in miRNA expression have been identified in a large number of cancer types. MiRNAs also have both oncogenic and tumour-suppressive roles in breast cancer post-transcriptional gene regulation. Breast cancer is a genetic disease and we performed miRNA analysis in human breast cancer cell lines to identify miRNAs in association with HSPs and pseudogenes by employing CellMiner; a web-based suite. CellMiner integrates several database and help analysis of microarray metadata. The experimental data provides a platform for researcher to compare macromolecules relationships in NCI-60 cell lines. Breast cancer associated miRNAs gathered from literature and analyzed by employing this suite, significantly correlated HSP genes and pseudogenes in breast cancer are determined as; HSPA13, HSP90AB1, TRAP1, HSPB1, DNAJB4, HSPD1 and HSP90AA4P, HSPB1P1, DNAJC8P1, HSPD1P9 respectively. HSPs involved in breast cancer are regulated by several miRNAs and miRNA regulators from CellMiner data found as hsa-miR-17, hsa-miR-22, hsa-miR-93, hsa-miR-106a, hsa-miR-125b, hsa-miR-130a, and hsa-miR-141. Cross check of the determined miRNAs and target HSPs were performed by target site prediction software. Comparison of the experimental data from CellMiner and software predicted data indicates differences. CellMiner data provides a vast miRNA types compared to that of prediction program and reported miRNAs in the literature. Therefore, reported key miRNAs in this work which are not studied earlier may help cancer researchers to uncover novel posttranslational regulation mechanisms. Cancer cells use HSP network as an escape mechanism from apoptosis, therefore inhibition of associated HSPs by modulating miRNAs may provide a novel therapy for the tumorigenesis.
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Jun 27, 2014

Adonis Hazoumé