Double siRNA-targeting of cIAP2 and LIVIN results in synergetic sensitization of HCT-116 cells to oxaliplatin treatment

Abstract

PurposeMost colon cancers show low sensitivity to treatment with oxaliplatin and a specific strategy is needed to overcome this problem. Our approach uses RNA interference to silence the expression of target genes responsible for the development of oxaliplatin resistance. Profile analysis of genes related to the regulation of apoptosis allowed identification of target genes showing the greatest degree of upregulation in response to oxaliplatin exposure.MethodsWe designed a panel of genes with functions closely related to inactivation of the caspase cascade, endoplasmic reticulum stress reduction, and drug metabolism. The candidate genes were silenced by means of specific small interfering RNA (siRNA) oligonucleotides.ResultsThe caspase 3 and 9 inhibitors of apoptosis 2 (cIAP2) and LIVIN were found to be the most dose-responsive genes during the period of oxaliplatin treatment. Two-fold sensitization of cells to oxaliplatin was observed with independent knockdown of either cIAP2 or LIVIN expression. siRNA-silencing of both targets produced a five-fold increase in oxaliplatin sensitivity of HCT-116 cells.ConclusionA dose-dependent approach revealed reliable targets for siRNA-silencing under low doses of oxaliplatin. Targeting the key proapoptotic chain with several specific siRNAs resulted in synergetic sensitization of HCT-116 cells to oxaliplatin treatment.

Silencing thelivingene enhances the cytotoxic effects of anticancer drugs on colon cancer cells

“…In other studies, silencing of livin reduced drug resistance to chemotherapy in glioblastoma, melanoma, and lung cancer [121314]. In addition, several studies have reported a synergetic anticancer effect when silencing of the livin gene is combined with chemotherapy [1516171819]. …”

Inhibition of livin expression suppresses cell proliferation and enhances chemosensitivity to cisplatin in human lung adenocarcinoma cells

“…Livin, a novel member of the inhibitor of apoptosis (IAP) protein family, is not detected in the majority of normal tissues, however, is highly expressed in various types of human malignancy (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Increased activity of this protein may be used as a reliable prognostic factor for initial and late resistance to chemotherapeutic drugs in certain types of human tumor (31)(32)(33)(34)(35)(36)(37).…”