β-Carotene induces apoptosis and up-regulates peroxisome proliferator-activated receptor γ expression and reactive oxygen species production in MCF-7 cancer cells

Although the pharmacological role of β-carotene in the prevention and treatment of many cancer cells has received increasing attention, the molecular mechanisms underlying such chemopreventive activity are not clear. Since peroxisome proliferator-activated receptor γ (PPAR-γ) has been implicated in regulating breast cancer cell differentiation and apoptosis, the effects of β-carotene on the PPAR-γ-mediated pathway and its association with reactive oxygen species production in MCF-7 cells were investigated in the present study. The results demonstrated that β-carotene significantly increased PPAR-γ mRNA and protein levels in time-dependent manner. In addition, β-carotene increased the cyclin-dependent kinase inhibitor p21WAF1/CIP1 expression and decreased the prostanoid synthesis rate-limiting enzyme cyclooxygenase-2 expression. 2-chloro-5-nitro-N-phenylbenzamide (GW9662), an irreversible PPAR-γ antagonist, partly attenuated the cell death caused by β-carotene. Further, reactive oxygen species (ROS) production was induced by β-carotene, resulting in mitochondrial dysfunction and cytochrome C release. Reduced glutathione (GSH) treatment decreases the intracellular ROS and prevents cytochrome C release and cell apoptosis induced by β-carotene. In total, these observations suggest that the synergistic effect of PPAR-γ expression and ROS production may account for β-carotene-mediated anticancer activities.