Curcumin, a phytochemical in turmeric, has been studied as a potential anticancer drug targeting multiple signaling molecules. However, the role of Src and Ras signaling pathways in curcumin sensitivity remains unknown. We investigated therefore the molecular mechanism of anti-proliferative and apoptosis-inducing activities of curcumin in HAG-1 human gallbladder adenocarcinoma cells transfected with either activated Src (HAG/src3-1) or Ras (HAG/ras5-1). Effects of curcumin on proliferation, apoptosis, cell cycle perturbation, and signal proteins for survival, proliferation, and apoptosis were evaluated by WST-1 assay, FACS analyses and Western blotting. Activation of either Src or Ras did not confer resistance to curcumin compared to HAG/neo3-5 vehicle-transfected cells, producing similar IC50 concentrations of curcumin among these 3 cell lines. Upon treatment with curcumin, constitutive activities of Erk1/2 were enhanced, but those of Akt were significantly inhibited in these three cell lines, with subsequent reductions of activities of downstream mTOR and S6K1. The sub-G0/G1 apoptotic cell populations were substantially increased in all cell lines with demonstrable cleavage of PARP, but this increase was most prominent in Src-activated cells. Reduced expression and phosphorylation of Bcl-2 and enhanced expression of Bax were demonstrated to have a causative role for the curcumin-induced apoptosis in Src-driven, but not Ras-driven cells. By contrast, drastic increases of the proportion of cells in a G2/M phase were seen in Ras-activated cells, suggesting a potential role of Ras/Erk1/2 activation in curcumin-induced G2/M cell cycle arrest. These data indicate that curcumin-induced growth declines would be mediated mainly by G2/M arrest of the cell cycle in Ras-driven cells but by apoptosis induction in Src-driven cells. Taken together, the results indicate that curcumin exhibits differential activities against apoptosis and cell cycle progression, depending on activation mechanisms of signal transduction, and that curcumin can overcome Src- and Ras-driven activation of downstream signaling pathways, thus providing evidence of potential application of curcumin for the treatment of human cancers with activated Src or Ras.

Citation Format: Misaki Ono, Takako Higuchi, Mikako Takeshima, Chen Chen, Shuji Nakano. Differential anti-tumor activities of curcumin against apoptosis and cell Cycle progression in Src- and Ras-activated human gallbladder carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2575. doi:10.1158/1538-7445.AM2013-2575