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Exposure of mammalian cells to heat stress causes impairment of numerous physiological functions and activates a number of signaling pathways. Some of these pathways, such as induction of heat-shock proteins and activation of Akt, enhance the ability of cells to survive heat stress. On the other hand, heat stress can trigger cell-death signaling via activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/Jnk). Recently, it has been shown that kinases activated by heat stress can regulate synthesis and functioning of the molecular chaperones, and these chaperones modulate the activity of the cell death and survival pathways. We have found that Akt plays a central role in determining the fate of L929 fibroblast cells exposed to heat stress. In our experiments heat stress causes Akt depletion and L929 cells to undergo cell death. Heat-shock protein 70 (Hsp70) is known to prevent stress-induced cell death by interfering with the SAPK/Jnk signaling pathway. In our study, there is a very high level of induction of Hsp70, yet this is not sufficient to rescue Akt depletion and L929 from cell death. The Akt depletion is specific, since actin protein level does not change during the heat stress. Moreover, our studies show that L929 cells can recover from a short-term heat shock, whereby, Akt level is returned to normal following recovery from heat shock. Therefore, it appears that the fate of the prolonged heat-stressed fibroblast cells is determined by Akt level, and that return of Akt protein level to normal prevents cell death.

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. [ABSTRACT FROM AUTHOR]