Caffeic acid derivatives inhibit the growth of colon cancer: Involvement of the PI3-K/Akt and AMPK signaling pathways

En Pei Isabel Chiang, Shu Yao Tsai, Yueh Hsiung Kuo, Man Hui Pai, Hsi Lin Chiu, Raymond L. Rodriguez, Feng Yao Tang

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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 G0/G1 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.

Original languageEnglish
Article numbere99631
JournalPLoS One
Volume9
Issue number6
DOIs
Publication statusPublished - Jun 24 2014

Fingerprint

AMP-activated protein kinase
AMP-Activated Protein Kinases
caffeic acid
colorectal neoplasms
Colonic Neoplasms
Colorectal Neoplasms
phosphotransferases (kinases)
Phosphotransferases
chemical derivatives
Derivatives
Assays
Growth
esters
Cells
Sirolimus
Neoplasms
G1 Phase Cell Cycle Checkpoints
Heterografts
assays
AMP-activated protein kinase kinase

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Caffeic acid derivatives inhibit the growth of colon cancer : Involvement of the PI3-K/Akt and AMPK signaling pathways. / Chiang, En Pei Isabel; Tsai, Shu Yao; Kuo, Yueh Hsiung; Pai, Man Hui; Chiu, Hsi Lin; Rodriguez, Raymond L.; Tang, Feng Yao.

In: PLoS One, Vol. 9, No. 6, e99631, 24.06.2014.

Research output: Contribution to journalArticle

Chiang, En Pei Isabel ; Tsai, Shu Yao ; Kuo, Yueh Hsiung ; Pai, Man Hui ; Chiu, Hsi Lin ; Rodriguez, Raymond L. ; Tang, Feng Yao. / Caffeic acid derivatives inhibit the growth of colon cancer : Involvement of the PI3-K/Akt and AMPK signaling pathways. In: PLoS One. 2014 ; Vol. 9, No. 6.
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