Inhibitory effect of snake venom toxin on NF-kappa B activity prevents human cervical cancer cell growth via increase of death receptor 3 and 5 expression

Abstract

We previously found that snake venom toxin inhibits nuclear factor kappa B (NF-kappa B) activity in several cancer cells. NF-kappa B is implicated in cancer cell growth and chemoresistance. In our present study, we investigated whether snake venom toxin (SVT) inhibits NF-kappa B, thereby preventing human cervical cancer cell growth (Ca Ski and C33A). SVT (0-12 mu g/ml) inhibited the growth of cervical cancer cells by the induction of apoptotic cell death. These inhibitory effects were associated with the inhibition of NF-kappa B activity. However, SVT dose dependently increased the expression of death receptors (DRs): DR3, DR5 and DR downstream pro-apoptotic proteins. Exploration of NF-kappa B inhibitor (Phenylarsine oxide, 0.1 mu M) synergistically further increased SVT-induced DR3 and DR5 expressions accompanied with further inhibition of cancer cells growth. Moreover, deletion of DR3 and DR5 by small interfering RNA significantly abolished SVT-induced cell growth inhibitory effects, as well as NF-kappa B inactivation. Using TNF-related apoptosis-inducing ligand resistance cancer cells (A549 and MCF-7), we also found that SVT enhanced the susceptibility of chemoresistance of these cancer cells through down-regulation of NF-kappa B, but up-regulation of DR3 and DR5. In vivo study also showed that SVT (0.5 and 1 mg/kg) inhibited tumor growth accompanied with inactivation of NF-kappa B. Thus, our present study indicates that SVT could be applicable as an anticancer agent for cervical cancer, or as an adjuvant agent for chemoresistant cancer cells.