Stimulated upregulation of HO-1 is associated with inadequate response of gastric and ovarian cancer cell lines to hyperthermia and cisplatin treatment.

Abstract

Heme oxygenase (HO)-1 is a heat shock protein induced by hyperthermia, responsible for cellular resistance to temperature. The aim of this in vitro study was to clarify the response of gastric and ovarian cancer cells to hyperthermic intraperitoneal chemotherapy, following the modulation of HO-1 expression. AGS and OVCAR-3 cells were treated with different temperature regimens, either alone or in combination with an IC50 dose of cisplatin for 1 h. Prior to treatment, HO-1 expression was silenced by short interfering RNA transfection. In OVCAR-3 cells, cisplatin increased HO-1 mRNA expression by 3.73-fold under normothermia and 2.4-fold under hyperthermia; furthermore, these factors similarly increased HO-1 protein expression levels. Exposure to cisplatin under hyperthermia reduced the viability of OVCAR-3 cells by 36% and HO-1-silencing enhanced this effect by 20%. HO-1-silencing under normothermia increased apoptotic rates in cisplatin-treated OVCAR-3 cells by 2.07-fold, and hyperthermia enhanced the effect by 3.09-fold. Semi-quantitative polymerase chain reaction (PCR) cell analysis indicated that exposure to cisplatin decreased the cell index under normothermia, and that hyperthermia boosted this effect in OVCAR-3. In AGS cells, only temperature increased cellular HO-1 levels. Silencing HO-1 in AGS cells at 37°C reduced viability by 16% and increased apoptotic rates 2.63-fold. Hyperthermia did not affect AGS viability; however, apoptosis was increased 6.84-fold. PCR analysis indicated no additional effects of hyperthermia on the AGS cell index. HO-1 is induced in cancer cells by different stressors in a variable manner. In tumors with highly inducible HO-1, prior silencing of this gene could improve the cellular response to hyperthermia and cisplatin.