Toyocamycin Induces Apoptosis Via the Crosstalk Between Reactive Oxygen Species and P38/ERK MAPKs Signaling Pathway in Human Prostate Cancer PC-3 Cells

Background: Toyocamycin, an antibiotic agent isolated from Streptomyces species, has been shown to have anticancer and chemopreventive effects on various cancer cells. Until now, Toyocamycin-induced apoptosis has not been reported to be involved in the regulation between mitogen-activated protein kinases (MAPKs) and reactive oxygen species (ROS) production.

Methods: Cell viability assay, western blot, cell-cycle arrest, annexin V/propidium iodide assay, reactive oxygen species (ROS) production, mitochondrial membrane potential and intracellular Ca flux were assayed.

Results: We investigated the apoptotic effect of Toyocamycin and the underlying molecular mechanism in prostate cancer PC-3 cells. Toyocamycin treatment resulted in reduced cell viability of PC-3 cells, but not of non-malignant RWPE-1 cells. Toyocamycin enhanced apoptosis, mitochondrial dysfunction, and ROS production in PC-3 cells. In addition, MAPK proteins were activated upon Toyocamycin treatment. The p38 and extracellular signal-regulated kinases (ERK) activities were regulated by ROS-mediated signaling pathway underlying the Toyocamycin-induced apoptosis. Pretreatment with N-acetyl-l-cysteine (NAC) recovered the Toyocamycin-induced mitochondrial dysfunction, ROS, and apoptosis. Additionally, p38 stimulated ROS production and inhibitory effects on ERK activation, while ERK inhibited the ROS production and had no effect on p38 activation.

Conclusion: ROS-mediated activation of p38/ERK partially contributes to Toyocamycin-induced apoptosis, and p38/ERK MAPKs regulate the ROS production in PC-3 cells.