Heat Shock Protein 70 Inhibits Apoptosis in Cancer Cells Through Simultaneous and Independent Mechanisms

Vikas Dudeja, Nameeta Mujumdar, Phoebe Phillips, Rohit Chugh, Daniel Borja-Cacho, Rajinder K. Dawra, Selwyn M. Vickers, Ashok K. Saluja

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85 Scopus citations

Abstract

Background & Aims: Heat shock proteins (HSPs) are highly conserved and serve a multitude of functions that mediate cell survival. HSP70, the only inducible form of the 70-kilodalton subfamily of HSPs, is overexpressed in pancreatic cancer cells and has been shown to inhibit caspase-dependent apoptosis. We aimed to elucidate the mechanism by which HSP70 inhibits apoptosis in cancer cells. Methods: HSP70 expression was down-regulated in cultured pancreatic cancer cells by exposure to quercetin, triptolide, or short interfering RNAs. Intracellular Ca2+, cytosolic cathepsin B activity, caspase-3 activity, cell viability, and lysosome integrity were measured using colorimetric assays. Immunofluorescence assays were used to localize cathepsin B and Lamp2. BAPTA-AM was used to chelate intracellular Ca2+. Results: Inhibition of HSP70 increased intracellular Ca2+ levels in pancreatic and colon cancer cell lines and led to loss of lysosome integrity in pancreatic cancer cells. The release of intracellular Ca2+ and lysosomal enzymes activated caspase-dependent apoptosis independently and simultaneously. Conclusions: HSP70 inhibits apoptosis in cancer cells by 2 mechanisms: attenuation of cytosolic calcium and stabilization of lysosomes. HSP70-mediated cell survival might occur in other types of cancer cells.

Original languageEnglish (US)
Pages (from-to)1772-1782
Number of pages11
JournalGastroenterology
Volume136
Issue number5
DOIs
StatePublished - May 2009

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    Dudeja, V., Mujumdar, N., Phillips, P., Chugh, R., Borja-Cacho, D., Dawra, R. K., Vickers, S. M., & Saluja, A. K. (2009). Heat Shock Protein 70 Inhibits Apoptosis in Cancer Cells Through Simultaneous and Independent Mechanisms. Gastroenterology, 136(5), 1772-1782. https://doi.org/10.1053/j.gastro.2009.01.070