Lee Yun-Kyoung, Park Song Yi, Kim Young-Min, Park Ock Jin
Department of Food and Nutrition, Hannam University Daedeok Valley Campus, Yuseong-gu, Daejeon, Korea.
Ann N Y Acad Sci. 2009 Aug;1171:489-94. doi: 10.1111/j.1749-6632.2009.04699.x.
AMP-activated protein kinase (AMPK), a highly conserved protein in eukaryotes, functions as a major metabolic switch to maintain energy homeostasis. It also intrinsically regulates the mammalian cell cycle. Moreover, the AMPK cascade has emerged as an important pathway implicated in cancer control. In this study we investigated the effects of curcumin on apoptosis and the regulatory effect of the AMPK-cyclooxygenase-2 (COX-2) pathway in curcumin-induced apoptosis. Curcumin has shown promise as a chemopreventive agent because of its in vivo regression of various animal-model colon cancers. This study focused on exploiting curcumin to apply antitumorigenic effects through modulation of the AMPK-COX-2 cascade. Curcumin exhibited a potent apoptotic effect on HT-29 colon cancer cells at concentrations of 50 micromol/L and above. These apoptotic effects were correlated with the decrease in pAkt and COX-2, as well as the increase in p-AMPK. Cell cycle analysis showed that curcumin induced G(1)-phase arrest. Further study with AMPK synthetic inhibitor Compound C has shown that increased concentrations of Compound C would abolish AMPK expression, accompanied by a marked increase in COX-2 as well as pAkt expression in curcumin-treated HT-29 cells. By inhibiting AMPK with Compound C, we found that curcumin-treated colon cancer cells were no longer undergoing apoptosis; rather, they were proliferative. These results indicate that AMPK is crucial in apoptosis induced by curcumin and further that the pAkt-AMPK-COX-2 cascade or AMPK-pAkt-COX-2 pathway is important in cell proliferation and apoptosis in colon cancer cells.
AMP 激活的蛋白激酶（AMPK）是真核生物中一种高度保守的蛋白，作为主要的代谢开关来维持能量稳态。它还可内在调节哺乳动物细胞周期。此外，AMPK 级联反应已成为癌症控制中的一条重要途径。在本研究中，我们调查了姜黄素对细胞凋亡的影响以及 AMPK - 环氧化酶 -2（COX -2）途径在姜黄素诱导的细胞凋亡中的调节作用。姜黄素因其能使多种动物模型结肠癌在体内消退，已显示出作为化学预防剂的潜力。本研究聚焦于通过调节 AMPK - COX -2 级联反应来利用姜黄素发挥抗肿瘤作用。姜黄素在浓度为 50 μmol/L 及以上时对 HT -29 结肠癌细胞表现出显著的凋亡作用。这些凋亡作用与 pAkt 和 COX -2 的减少以及 p - AMPK 的增加相关。细胞周期分析表明姜黄素诱导 G1 期阻滞。使用 AMPK 合成抑制剂 Compound C 的进一步研究表明，在姜黄素处理的 HT -29 细胞中，Compound C 浓度增加会消除 AMPK 表达，同时伴随着 COX -2 以及 pAkt 表达的显著增加。通过用 Compound C 抑制 AMPK，我们发现姜黄素处理的结肠癌细胞不再发生凋亡；相反，它们开始增殖。这些结果表明 AMPK 在姜黄素诱导的细胞凋亡中起关键作用，进一步表明 pAkt - AMPK - COX -2 级联反应或 AMPK - pAkt - COX -2 途径在结肠癌细胞的增殖和凋亡中起重要作用。
