Prodigiosin-induced cytotoxicity involves RAD51 down-regulation through the JNK and p38 MAPK pathways in human breast carcinoma cell lines

Chien-Hsing Lu, Shin-Chang Lin, Shu-Yi Yang, Mu-Yun Pan, Yun-Wei Lin, Chun-Yi Hsu, Yu-Hong Wei, Jo-Shu Chang, Chia-Che Chang
Toxicology Letters 2012 July 7, 212 (1): 83-9
RAD51 is essential for homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs) in mammalian cells. RAD51 is an attractive target for anticancer drugs, given high RAD51 levels are frequently observed in many human tumors and associated with increased resistance to DSBs-inducing chemotherapeutics. Prodigiosin is a bacterial tripyrrole pigment with potent anticancer activity and also provokes DSBs. We hereby aimed to elucidate the role of RAD51 in prodigiosin-induced cytotoxicity. Prodigiosin was found to down-regulate RAD51 in multiple human breast carcinoma cell lines irrespective of p53 status. Mechanistically, prodigiosin lowered RAD51 mRNA expression, whereas blockade of proteasome-mediated degradation failed to restore RAD51 levels following prodigiosin treatment. In addition, prodigiosin triggered phosphorylation of JNK and p38 MAPK, while pharmacological inhibition of JNK or p38 MAPK attenuated prodigiosin-mediated inhibition of RAD51 mRNA expression. Lastly, cells with enforced RAD51 expression showed increased resistance to prodigiosin-induced cytotoxicity as well as inhibition of colony formation. Collectively, we conclude that RAD51 down-regulation represents one of the modes of prodigiosin's cytotoxic action, ostensibly by augmenting the genotoxic effect of prodigiosin through suppression of RAD51-mediated HR repair. Our findings further implicate the use of prodigiosin to potentiate the cytotoxicity of DSB-inducing chemotherapeutics through RAD51 down-regulation.

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