Selenium is a promising chemopreventive agent for
prostate cancer, possibly via an induction of apoptosis. Earlier studies have shown that
selenite induces
DNA single strand breaks (SSBs),
reactive oxygen species (ROS), p53 Ser-15 phosphorylation and
caspase-dependent and -independent apoptosis, whereas a
methylselenol precursor
methylseleninic acid (MSeA) induces
caspase-mediated apoptosis regardless of p53 status. Here we address three main questions: What types of ROS are induced by
selenite vs. MSeA in LNCaP (p53 wild type,
androgen-responsive) and DU145 (mutant p53,
androgen-independent)
prostate cancer cells? Does ROS generation depend on
androgen signaling? What are the relationships among ROS,
DNA SSBs, p53 and
caspases? We show that
selenite (5 microM) induced
superoxide and
hydrogen peroxide in LNCaP cells much more than in DU145 cells and the ROS generation was not affected by physiological
androgen stimulation. MSeA (10 microM) induced apoptosis without either type of ROS in both cell lines. In LNCaP cells, we established
superoxide as a primary mediator for
selenite-induced
DNA SSBs, p53 activation and
caspase-mediated apoptosis. Furthermore a p53-dominant negative mutant attenuated
selenite-induced ROS, leading to a proportionate protection against apoptosis. The results support the p53-mitochondria axis in a feedback loop for sustaining
superoxide production to lead to efficient
caspase-mediated apoptosis by
selenite. In contrast,
caspase-mediated apoptosis induced by MSeA does not involve ROS induction. Since p53 is frequently mutated or deleted in
prostate cancer and many other
cancers, our results suggest that genotoxic vs. nongenotoxic classes of
selenium may exert differential apoptosis efficacy depending on the p53 status of the
cancer cells.