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

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 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.

RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

“…20,47,[71][72][73][74][75] However, similar to MAPK1/3 activation, activation of MAPK11/12/13/14 by ER stress was not affected by knockdown of RIPK1 in melanoma cells under ER stress as detected using an antibody against phosphorylated MAPK11/12/13/14 in western blot analysis, suggesting that neither MAPK1/3 nor MAPK11/12/13/14 plays a part in RIPK1-mediated induction of autophagy by ER stress (Fig. S8).…”

Autophagy and Cancer Therapy

“…Another natural product, triterpenoid saponins isolated from soybeans, induces autophagy in colon cancer cells with downregulation of Akt and upregulation of ERK. 18,19 In addition, a vitamine D analog, EB1089, induces autophagy in MCF-7 cells with partially condensed chromatin; Beclin 1 overexpression sensitizes these cells to EB 1089. 20 Interestingly, silencing Beclin 1 also inhibits cell proliferation in these cancer cells.…”

Hyperoside induces both autophagy and apoptosis in non-small cell lung cancer cells in vitro

“…Several anti-cancer agents are known to inhibit the PI3K/Akt/mTOR/p70S6K pathway, resulting in induction of autophagy in tumor cell lines [17] . In this study, we found that hyperoside treatment significantly decreased the expression levels of phospho-Akt (Ser473), phospho-mTOR, phospho-p70S6K (Thr389) and phospho-4E-BP1 (Thr37/46) in A549 cells.…”

“…As shown in Figure 3D, treatment with hyperoside caused marked decreases in phosphorylated Akt in a concentration-dependent manner. In addition, increased activity of ERK1/2 has been reported to be required for induction of autophagy [17] . Therefore, we investigated whether hyperoside increases the level of phosphorylated ERK1/2, a key regulator of autophagy downstream of Akt.…”

“…Constitutive activation of the PI3K/Akt/ mTOR pathway occurs in 90% of NSCLC cell lines [15] . Several anti-cancer agents are known to inhibit the PI3K/Akt/mTOR/ p70S6K pathway and simultaneously activate extracellular signal-regulated kinase (ERK1/2), resulting in induction of autophagy in tumor cell lines [16,17] . In accordance with this observation, treatment with the mTOR inhibitor rapamycin was associated with a 90% reduction in carcinogen-induced lung tumors in a murine model [18] .…”