Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2009-05, Vol.136 (5), p.1772-1782

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2009

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.