Heat-shock protein expression in cisplatin-sensitive and -resistant human tumor cells

Abstract

It has been suggested that the expression of certain heatshock proteins (HSPs) may be prognostic markers in several tumor types. Since HSPs may be involved in determining cellular sensitivity to chemotherapeutic drugs, the possible relation between HSP expression and cisplatin (cDDP) sensitivity was studied. Three human germ-cell tumor cell lines, I human small-cell lung carcinoma (SCLC) cell line and 3 human colon carcinoma cell lines were used as a model for differences in intrinsic cDDP sensitivity. The constitutive expression of a panel of HSPs was studied by immunoblotting. No correlation was found between expression of HSP90, HSP73, HSP72, HSP60 and HSP27 and the extent of intrinsic cDDP sensitivity when all cell lines studied were considered. However, for the 3 cell lines derived from germ-cell carcinomas, HSP27 expression was inversely related t o cDDP sensitivity; i.e. decreased HSP27 levels were associated with decreased sensitivity. Constitutive HSP expression was also studied in 2 sets of human cell lines with in vitro acquired cDDP resistance. In both resistant cell lines, decreased expression of HSP27 (as determined by Western blotting) was found as compared to the sensitive parent cell lines. Thus, acquired resistance to cDDP was also accompanied by decreased HSP27 expression. Interestingly, when basal HSP27 mRNA levels were measured in the SCLC cell line (GLC,) and its subline with acquired resistance (GLC4-cDDP), no significant differences were detected. Continuous cDDP incubation increased HSP27 levels and induced HSP27 phosphorylation in GLC4 cells, but not in the resistant subline. Thus, although no general relationships between HSP expression and cDDP sensitivity are apparent, high HSP27 expression in vitro relates to high sensitivity to cDDP treatment in some tumor types. This is in accordance with reported clinical data on high HSP27 levels in tumors correlating with good prognosis.o 1996 Wiley-Liss, Inc.

Combination of hyperthermia and bortezomib results in additive killing in mantle cell lymphoma cells

“…This effect was found regardless of the thermal dose applied, indicating that the degree of inducible HSPs, which are higher after a more severe thermal stress, is not critical in conferring or impacting resistance. This observation is consistent with previous evidence that tumor cells with more HSPs are not more resistant to chemotherapy than those with low basal levels [30]. Most importantly, it disproves the hypothesis that pre-treatment of cells with heat shock results in an increased resistance to proteasome inhibitors [27,31].…”

Expression of Stress-related Genes in a Cadmium-resistant A549 Human Cell Line

“…Acquired resistance to the chemotherapeutic drug cisplatin was also found to be accompanied by a decreased HSP27 expression (Hettinga et al, 1996). HSP27 overexpression is generally thought to protect against apoptosis triggered by a variety of stimuli, including oxidative stress generated by tumor necrosis factor (TNF) (Mehlen et al, 1996a).…”

Quercetin Enhances Susceptibility to NK Cell-mediated Lysis of Tumor Cells Through Induction of NKG2D Ligands and Suppression of HSP70

“…These results demonstrated that quercetin could enhance susceptibility of the tumor cells to NK cell-mediated lysis through induction of NKG2D ligands in tumor cells. As HSPs are closely associated with apoptotic resistance and make tumor cells resistant to anticancer therapies, 26 to NK cell-mediated lysis. Then it could be determined whether overexpression of HSP70 reverses the effect of quercetin on the susceptibility of SNU-C4 cells to NK-92 cells.…”

“…[16][17][18][19] However, many of these treatments such as 5-fluorouracil, cisplatin, valporic acid, tricostatin A, bortezomib, ionizing radiation, and heat shock of tumor cells, have also been shown to induce heat-shock proteins (HSPs), 20-25 which protect tumor cells from stress conditions and apoptosis. 26,27 As it has been known that the induced HSPs are associated with the resistance of tumor cells to anticancer therapies, [28][29][30] it could be suggested that enhancing the cytotoxicity of NK cells through the induction of NK cells-activating ligands would be limited by the chaperone effects of the HSPs that were simultaneously induced in the tumor cells. An earlier report showed that down-regulation of HSPs in tumor cells could increase the susceptibility to NK cell-mediated cytotoxicity, when tumor cells were treated with ATO, an inducer of NKG2D ligands.…”