Par-4 regulates autophagic cell death in human cancer cells via upregulating p53 and BNIP3

Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that selectively induces apoptosis in cancer cells. Although the mechanism of Par-4-mediated induction of apoptosis has been well studied, the involvement of Par-4 in other mechanisms of cell death such as autophagy is unclear. We investigated the mechanism involved in Par-4-mediated autophagic cell death in human malignant glioma. We demonstrate for the first time that the tumor suppressor lipid, ceramide (Cer), causes Par-4 induction, leading to autophagic cell death in human malignant glioma. Furthermore, we identified the tumor suppressor protein p53 and BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) as downstream targets of Par-4 during Cer-mediated autophagic cell death. RNAi-mediated down-regulation of Par-4 blocks Cer-induced p53-BNIP3 activation and autophagic cell death, while upregulation of Par-4 augmented p53-BNIP3 activation and autophagic cell death. Remarkably, in many instances, Par-4 overexpression alone was sufficient to induce cell death which is associated with features of autophagy. Interestingly, similar results were seen when glioma cells were exposed to classical autophagy inducers such as serum starvation, arsenic trioxide, and curcumin. Collectively, the novel Par-4-p53-BNIP3 axis plays a crucial role in autophagy-mediated cell death in human malignant glioma.