Sensitization of Cervical Carcinoma Cells to Paclitaxel by an IPP5 Active Mutant

Abstract

Paclitaxel is one of the best anticancer agents that has been isolated from plants, but its major disadvantageis its dose-limiting toxicity. In this study, we obtained evidence that the active mutant IPP5 (8-60hIPP5m), thelatest member of the inhibitory molecules for protein phosphatase 1, sensitizes human cervix carcinoma cellsHeLa more efficiently to the therapeutic effects of paclitaxel. The combination of 8-60hIPP5m with paclitaxelaugmented anticancer effects as compared to paclitaxel alone as evidenced by reduced DNA synthesis andincreased cytotoxicity in HeLa cells. Furthermore, our results revealed that 8-60hIPP5m enhances paclitaxelinducedG2/M arrest and apoptosis, and augments paclitaxel-induced activation of caspases and release ofcytochrome C. Evaluation of signaling pathways indicated that this synergism was in part related to downregulationof NF-ҝB activation and serine/threonine kinase Akt pathways. We noted that 8-60hIPP5m downregulatedthe paclitaxel-induced NF-ҝB activation, IқBα degradation, PI3-K activity and phosphorylation ofthe serine/threonine kinase Akt, a survival signal which in many instances is regulated by NF-ҝB. Together, ourobservations indicate that paclitaxel in combination with 8-60hIPP5m may provide a therapeutic advantage forthe treatment of human cervical carcinoma