Synthetic siRNA targeting heat shock protein 105 induces the apoptosis of various cancer cells both in vitro and in vivo. Free

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We previously reported that the heat shock protein 105 (HSP105), identified by a serological analysis of the recombinant cDNA expression library (SEREX) using the serum from a pancreatic cancer patient, was overexpressed in various human tumors and the testis in adult human tissues by immunohistochemical analysis. In the present study, to elucidate the biological function of HSP105 protein in cancer cells, we first established NIH3T3 cells overexpressing murine HSP105 (NIH3T3-HSP105). The NIH3T3-HSP105 cells acquired resistance to apoptosis induced by heat shock or doxorubicin. The siRNA-mediated suppression of HSP105 protein expression induced apoptosis in human cancer cells but not in fibroblasts. By the combination of siRNA introduction and doxorubicin or heat shock treatment, apoptosis was synergistically induced in a human colon cancer cell line, HCT116 cells. In vivo, siRNA inoculation into a human gastric cancer cell line KATO-3 tumor established in the flank of an NOD SCID mouse suppressed the tumor growth. This siRNA-induced apoptosis was mediated through caspases, but not p53 tumor suppressor protein, even though the HSP105 protein was bound to wild type p53 protein in HCT116 cells. These findings suggest that the constitutive overexpression of HSP105 in cancer cells is therefore involved in malignant transformation by protecting tumor cells from apoptosis. HSP105 may thus be a novel target molecule for cancer therapy and the treatment regimen using synthetic siRNA to suppress the expression of HSP105 protein may therefore provide a new strategy for cancer therapy.