Journal Article

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

Allison A. Ellington, Mark A. Berhow and Keith W. Singletary

in Carcinogenesis

Volume 27, issue 2, pages 298-306
Published in print February 2006 | ISSN: 0143-3334
Published online August 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi214
Inhibition of Akt signaling and enhanced ERK1/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells

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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.

Keywords: MDC, monodansylcadaverine; PI3K, phosphotidyl-inositol-3-kinase; PIP3, phosphotidyl-inositol-3,4,5-phosphate; TSC, tuberous sclerosis complex

Journal Article.  6850 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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