Caffeic Acid Derivatives Inhibit the Growth of Colon Cancer: Involvement of the PI3-K/Akt and AMPK Signaling Pathways

被引:89
作者
Chiang, En-Pei Isabel [1 ,2 ,3 ]
Tsai, Shu-Yao [4 ]
Kuo, Yueh-Hsiung [5 ,6 ]
Pai, Man-Hui [7 ]
Chiu, Hsi-Lin [5 ,6 ]
Rodriguez, Raymond L. [8 ]
Tang, Feng-Yao [9 ]
机构
[1] Natl Chung Hsing Univ, Dept Food Sci & Biotechnol, Taichung 40227, Taiwan
[2] Natl Chung Hsing Univ, NCHU UCD Plant & Food Biotechnol Program, Taichung 40227, Taiwan
[3] Natl Chung Hsing Univ, Agr Biotechnol Ctr, Taichung 40227, Taiwan
[4] Asia Univ, Dept Hlth & Nutr Biotechnol, Taichung, Taiwan
[5] China Med Univ, Dept Chinese Pharmaceut Sci & Chinese Med Resourc, Taichung, Taiwan
[6] Asia Univ, Dept Biotechnol, Taichung, Taiwan
[7] Taipei Med Univ, Dept Anat, Taipei, Taiwan
[8] Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA
[9] China Med Univ, Dept Nutr, Biomed Sci Lab, Taichung, Taiwan
关键词
ACTIVATED PROTEIN-KINASE; PHENETHYL ESTER CAPE; TUMOR-GROWTH; CYCLIN D1; COLORECTAL-CANCER; EXPRESSION; CELLS; ENERGY; CONSUMPTION; PROGRESSION;
D O I
10.1371/journal.pone.0099631
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: The aberrant regulation of phosphatidylinositide 3-kinases (PI3-K)/Akt, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (m-TOR) signaling pathways in cancer has prompted significant interest in the suppression of these pathways to treat cancer. Caffeic acid (CA) has been reported to possess important anti-inflammatory actions. However, the molecular mechanisms by which CA derivatives including caffeic acid phenethyl ester (CAPE) and caffeic acid phenylpropyl ester (CAPPE), exert inhibitory effects on the proliferation of human colorectal cancer (CRC) cells have yet to be elucidated. Methodology/Principal Findings: CAPE and CAPPE were evaluated for their ability to modulate these signaling pathways and suppress the proliferation of CRC cells both in vitro and in vivo. Anti-cancer effects of these CA derivatives were measured by using proliferation assays, cell cycle analysis, western blotting assay, reporter gene assay and immunohistochemical (IHC) staining assays both in vitro and in vivo. This study demonstrates that CAPE and CAPPE exhibit a dose-dependent inhibition of proliferation and survival of CRC cells through the induction of G(0)/G(1) cell cycle arrest and augmentation of apoptotic pathways. Consumption of CAPE and CAPPE significantly inhibited the growth of colorectal tumors in a mouse xenograft model. The mechanisms of action included a modulation of PI3-K/Akt, AMPK and m-TOR signaling cascades both in vitro and in vivo. In conclusion, the results demonstrate novel anti-cancer mechanisms of CA derivatives against the growth of human CRC cells. Conclusions: CA derivatives are potent anti-cancer agents that augment AMPK activation and promote apoptosis in human CRC cells. The structure of CA derivatives can be used for the rational design of novel inhibitors that target human CRC cells.
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页数:17
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