Inhibition of Akt signaling and enhanced ERK1/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells

• Published in: Carcinogenesis (New York) Vol. 27; no. 2; pp. 298 - 306
• Main Authors: Ellington, Allison A., Berhow, Mark A., Singletary, Keith W.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-02-2006; Oxford Publishing Limited (England)
• Subjects: 5-phosphate; Autophagy; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Colonic Neoplasms - pathology; Fabaceae - chemistry; Gastroenterology. Liver. Pancreas. Abdomen; Humans; MDC; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; monodansylcadaverine; phosphotidyl-inositol-3; phosphotidyl-inositol-3-kinase; PI3K; PIP3; Proto-Oncogene Proteins c-akt - physiology; Saponins - pharmacology; Signal Transduction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; TSC; tuberous sclerosis complex; Tumor Cells, Cultured; Tumors; Terpenoid; Enzyme; Akt protein kinase; Mitogen-activated protein kinase; Malignant tumor; Biological activity; Colonic disease; Signal transduction; Colon cancer; Triterpene; Digestive diseases; Intestinal disease; Inhibitor; Inhibition; Tumor cell
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgi214

Triterpenoid B-group soyasaponins have been found to induce macroautophagy in human colon cancer cells at concentrations obtainable through consumption of legume foodstuffs. In the present studies the mechanism(s) for this autophagy-inducing action of soyasaponins was evaluated by measuring changes in signal transduction pathways associated with autophagy. Specifically, inhibition of the Akt signaling pathway and enhanced activity of ERK1/2 have previously been implicated in controlling induction of macroautophagy in mammalian cancer cells. Here we show that these pathways are also involved in B-group soyasaponin-induced macroautophagy, as changes in enzyme activities preceded significant increases in autophagic activity. The autophagic capacity of HCT-15 cells was significantly increased by 6 h post-saponin exposure, which led us to measure alterations in signaling events that preceded this time point. We determined that exposure to B-group soyasaponins suppressed Akt activity maximally by 50%, which was associated with a reduction in the activating phosphorylation of the Akt-serine473 residue. In addition, ERK1/2 activity was significantly increased by 60%, and was determined to be necessary for B-group soyasaponin-induced autophagy. The raf-1 kinase has been identified as a potential point of cross-talk between the Akt and ERK1/2 signaling cascades. Following B-group soyasaponin treatment activity of raf-1 was significantly increased by a maximal 200%, suggesting that this enzyme in part modulates the enhanced ERK1/2 activity. These results provide new insights into the signaling events that control induction of autophagy by B-group soyasaponins in human colon cancer cells and suggest that soyasaponins warrant further study as potential colon cancer chemopreventive agents.