The role of
selenium as potential
cancer chemopreventive and chemotherapeutic agents has been supported by epidemiological, preclinical and clinical studies. Although cell apoptosis has been evidenced as a critical mechanism mediating the anticancer activity of
selenium, the underlying molecular mechanisms remain elusive. In the present study, we showed that
selenocystine (SeC), a naturally occurring selenoamino
acid, induced
caspase-independent apoptosis in MCF-7
breast carcinoma cells, which was accompanied by
poly(ADP-ribose) polymerase (PARP) cleavage,
caspase activation, DNA fragmentation,
phosphatidylserine exposure and nuclear condensation. Moreover, SeC induced the loss of mitochondrial membrane potential (DeltaPsi(m)) by regulating the expression and phosphorylation of Bcl-2 family members. Loss of DeltaPsi(m) led to the mitochondrial release of
cytochrome c and
apoptosis-inducing factor (AIF) which subsequently translocated into the nucleus and induced
chromatin condensation and DNA fragmentation. MCF-7 cells exposed to SeC shown increase in total p53 and phosphorylated p53 on
serine residues of Ser15, Ser20, and Ser392 prior to
mitochondrial dysfunction. Silencing and attenuating of p53 activation with RNA interference and
pifithrin-alpha treatment, respectively, partially suppressed SeC-induced cell apoptosis. Furthermore, generation of
reactive oxygen species and subsequent induction of
DNA strand breaks were found to be upstream cellular events induced by SeC. The
thiol-reducing
antioxidants,
N-acetylcysteine and
glutathione, completely blocked the occurrence of cell apoptosis. Taken together, these results suggest that SeC, as a promising anticancer selenocompound, induces MCF-7 cell apoptosis by activating ROS-mediated mitochondrial pathway and p53 phosphorylation.