Submitted to: Carcinogenesis
Publication Type: Peer reviewed journal
Publication Acceptance Date: 8/11/2005
Publication Date: 2/1/2006
Citation: Ellington, A.A., Berhow, M.A., Singletary, K.W. 2006. Inhibition of Akt signaling and enhanced erk1/2 activity are involved in induction of macroautophagy by triterpenoid b-group soyasaponins in colon cancer cells. Carcinogenesis. 27(2):298-306. Interpretive Summary: Diets high in soybean products have been shown to lower the risk for getting certain chronic diseases such as cancer. The actual agents in soy that prevent these diseases have not yet been accurately determined. Soy contains a number of biologically active "nutraceuticals" which have not been examined for biological activity in human systems. One such group of nutraceuticals are the soy saponins. It was found in that treatment of cultured human colon cancer cells with soy saponin at levels found in a soy rich diet caused the cancer cells to go into a programmed "cell death." This indicates that diets rich in soy saponins may be able to slow or stop colon cancer development. These results presented in this paper provide new insights into the signaling events that control induction of cell death by B-group soyasaponins in human colon cancer cells and suggest that soyasaponins warrant further study as potential colon cancer chemopreventive agents.
Technical Abstract: 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 six hours 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.