Abstract
BackgroundThe 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 FindingsCAPE 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.ConclusionsCA 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.
Highlights
Colorectal cancer (CRC) is one of the leading causes of cancer and cancer mortality in many countries [1,2]
The IC50s for caffeic acid phenethyl ester (CAPE) and caffeic acid phenylpropyl ester (CAPPE) in human colorectal cancer (CRC) SW-480 cells are 132.3 mM and 130.7 mM, respectively. These results demonstrate that CAPE and CAPPE are each able to significantly inhibit the proliferation of human CRC cells in a dose-dependent manner
The results suggested that Caffeic acid (CA) derivatives act as chemopreventive agents against human CRC through a modulation of the phosphatidylinositide 3-kinases (PI3-K)/Akt and AMPK signaling pathways
Summary
Colorectal cancer (CRC) is one of the leading causes of cancer and cancer mortality in many countries [1,2]. Many studies have indicated that mutations of the phosphatidylinositide 3-kinase (PI3-K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) molecules are commonly observed in various types of cancer [3,4]. Oncogenic activation of PI3-K/Akt molecules enhances cell proliferation by increasing the cyclin D1 level [5,6]. It is well known that the aberrant expression of the cyclin D1 and Cdk proteins is involved in the proliferation of CRC cells [7]. Suppression of the PI3-K/Akt and MAPK/ERK signaling pathways leads to the blockade of cell proliferation and demonstrates the importance of these signaling cascades in the control of both cell cycle progression and cell growth during cancer development [4,8]. MMPs are zinc-dependent endopeptidases capable of degrading ECM components [11]. 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
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