ROS-dependent prostate apoptosis response-4 (Par-4) up-regulation and ceramide generation are the prime signaling events associated with curcumin-induced autophagic cell death in human malignant glioma

Malignant gliomas are extremely resistant to therapies that induce apoptosis, but are less resistant to therapies that induce autophagy. Therefore, drugs targeting autophagy are promising in the management of malignant gliomas. In this study, we investigated the anti-glioma potential of curcumin in vitro, and further examined the molecular mechanisms of curcumin-induced cell death in human malignant glioma. Here, we provide evidence that curcumin is cytotoxic against human malignant glioma cell lines, and the mechanism of cell death caused by curcumin is associated with features of autophagy. Curcumin suppresses the growth of human malignant glioma cells via ROS-dependent prostate apoptosis response-4 (Par-4) induction and ceramide generation. Extracellular supplementation of antioxidants such as glutathione and N-acetylcysteine to glioma cells abrogated the Par-4 induction, ceramide generation, and in turn, prevented curcumin-induced autophagic cell death. Moreover, tumor cells transfected with Par-4 gene sensitized the curcumin-induced autophagic cell death. Overall, this study describes a novel signaling pathway by which curcumin induces ROS-dependent Par-4 activation and ceramide generation, leading to autophagic cell death in human malignant glioma cells.