title: The PI3K/Akt pathway is involved in procyanidin-mediated suppression of human colorectal cancer cell growth.
abstract: Colorectal cancer (CRC) has the third highest incidence worldwide. Epidemiological studies showed that the consumption of fruit and vegetables containing procyanidins (PCA), polymers of flavan-3-ols, is associated with lower CRC risk. However, the molecular mechanisms supporting this positive association are unclear. This study investigated the capacity of PCA with different degrees of polymerization to reduce CRC cell growth, characterizing the underlying mechanisms. Compared to the monomer ((-)-epicatechin) and the trimer, the hexamer (Hex) was the most active at reducing CRC cell viability. Hex caused a concentration- (2.5-50 μM) and time- (24-72 h) dependent decrease in the viability of six human CRC cell lines in culture. Hex caused CRC apoptotic Caco-2 cell death within 24 h, as evidenced by caspase 3 and caspase 9 activation, DNA fragmentation, and changes in nuclear morphology/staining. Hex-induced apoptosis occurs through the mitochondrial pathway, as evidenced by an increased Bad mitochondrial translocation, and cytochrome c release from the mitochondria to the cytosol. Hex also arrested the Caco-2 cell cycle at G2/M phase and upregulated genes involved in autophagy. Mechanistically, in Caco-2 cells Hex inhibited the PI3K/Akt signaling pathway, causing the downstream downregulation of proteins involved in the regulation of cell survival (Bad, GSK-3β). Accordingly, the Akt inhibitor MKK-2206 decreased Bad and GSK-3β phosphorylation. MKK-2206 decreased cell growth, having an additive effect with Hex. In conclusion, our results show that large PCA can inhibit CRC cell growth via the Akt kinase pathway, demonstrating a mechanism to explain the epidemiological evidence linking PCA-rich diets with lower CRC risk. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Viticulture and Enology, University of California, Davis, California.
authors.forename: Ying Yng
authors.initials: YY
authors.lastname: Choy
authors.affiliation: Departments of Nutrition and Environmental Toxicology, University of California, Davis, California.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Fraga
authors.affiliation: Department of Preventive Medicine, Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York.
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Mackenzie
authors.affiliation: Department of Viticulture and Enology, University of California, Davis, California.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Waterhouse
authors.affiliation: Departments of Nutrition and Environmental Toxicology, University of California, Davis, California.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cremonini
authors.affiliation: Departments of Nutrition and Environmental Toxicology, University of California, Davis, California.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Oteiza
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D044946:Biflavonoids / Q000494:pharmacology*; D018938:Caco-2 Cells; D002392:Catechin / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D044945:Proanthocyanidins / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012007:Rectum / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D044946:Biflavonoids; D044945:Proanthocyanidins; C017674:procyanidin; D002392:Catechin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: apoptosis; autophagy; cell cycle arrest; proanthocyanidin