Although curcumin suppresses the growth of a variety of cancer cells, its poor absorption and low systemic bioavailability have limited its translation into clinics as an anticancer agent. In this study, we show that dimethoxycurcumin (DMC), a methylated, more stable analog of curcumin, is significantly more potent than curcumin in inducing cell death and reducing the clonogenicity of malignant breast cancer cells. Furthermore, DMC reduces the tumor growth of xenografted MDA-MB 435S cells more strongly than curcumin. We found that DMC induces paraptosis accompanied by excessive dilation of mitochondria and the endoplasmic reticulum (ER); this is similar to curcumin, but a much lower concentration of DMC is required to induce this process. DMC inhibits the proteasomal activity more strongly than curcumin, possibly causing severe ER stress and contributing to the observed dilation. DMC treatment upregulates the protein levels of CCAAT-enhancer-binding protein homologous protein (CHOP) and Noxa, and the small interfering RNA-mediated suppression of CHOP, but not Noxa, markedly attenuates DMC-induced ER dilation and cell death. Interestingly, DMC does not affect the viability, proteasomal activity or CHOP protein levels of human mammary epithelial cells, suggesting that DMC effectively induces paraptosis selectively in breast cancer cells, while sparing normal cells. Taken together, these results suggest that DMC triggers a stronger proteasome inhibition and higher induction of CHOP compared with curcumin, giving it more potent anticancer effects on malignant breast cancer cells.
The serine/threonine protein kinase, Akt/PKB, has an essential function in cell survival during response to various stresses. Recent studies have demonstrated that Akt isoforms exhibit some distinct physiological functions, but the isotype-specific functions for Akt in the stress response have not been fully identified. In this study, we analysed the cellular response to genotoxic stress using isogenic wild-type, Akt1À/À and Akt2 À/À mouse embryonic fibroblasts (MEFs). Marked hypersensitivity of Akt2MEFs was observed to UV irradiation, whereas wild-type and Akt1À/À MEFs showed comparable levels of resistance. Akt2À/À mouse aortic endothelial cells also showed hypersensitivity to UV and the reconstitution of Akt2 expression in the Akt2 À/À MEFs restored the UV resistance of the cells. Interestingly, upon UV irradiation, JNK and p38 were significantly upregulated in Akt2MEFs, compared to wild-type and Akt1 À/À MEFs. Additionally, inhibition of JNK and p38 activation reduced UV-induced cell death. Furthermore, both the hyperactivation of JNK and p38 and the UV-induced cell death in Akt2 À/À MEFs were completely inhibited by restoring Akt2 expression. These results indicate that Akt2, but not Akt1, is essential for cell survival upon UV irradiation, and that Akt2 prevents UV-induced cell death by inhibiting activation of JNK and p38.
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