The PI3K/Akt pathway is involved in procyanidin-mediated suppression of human colorectal cancer cell growth

Ying Yng Choy, Magdalena Fraga, Gerardo Mackenzie, Andrew L. Waterhouse, Eleonora Cremonini, Patricia I. Oteiza

Research output: Contribution to journalArticle

11 Citations (Scopus)

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- (2.5-50μM) and time- (24-72h) dependent decrease in the viability of six human CRC cell lines in culture. Hex caused CRC apoptotic Caco-2 cell death within 24h, 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.

Original languageEnglish (US)
JournalMolecular Carcinogenesis
DOIs
StateAccepted/In press - 2016

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Phosphatidylinositol 3-Kinases
Colorectal Neoplasms
Proanthocyanidins
Growth
Caco-2 Cells
Glycogen Synthase Kinase 3
Cell Survival
procyanidin
Caspase 9
Catechin
G2 Phase
Autophagy
DNA Fragmentation
Cytochromes c
Caspase 3
Polymerization
Vegetables
Cell Division
Cytosol
Epidemiologic Studies

Keywords

  • Apoptosis
  • Autophagy
  • Cell cycle arrest
  • Proanthocyanidin

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

The PI3K/Akt pathway is involved in procyanidin-mediated suppression of human colorectal cancer cell growth. / Choy, Ying Yng; Fraga, Magdalena; Mackenzie, Gerardo; Waterhouse, Andrew L.; Cremonini, Eleonora; Oteiza, Patricia I.

In: Molecular Carcinogenesis, 2016.

Research output: Contribution to journalArticle

Choy, Ying Yng ; Fraga, Magdalena ; Mackenzie, Gerardo ; Waterhouse, Andrew L. ; Cremonini, Eleonora ; Oteiza, Patricia I. / The PI3K/Akt pathway is involved in procyanidin-mediated suppression of human colorectal cancer cell growth. In: Molecular Carcinogenesis. 2016.
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AB - 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- (2.5-50μM) and time- (24-72h) dependent decrease in the viability of six human CRC cell lines in culture. Hex caused CRC apoptotic Caco-2 cell death within 24h, 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.

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