Abstract
BackgroundObesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene), a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established.MethodsWe investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity) and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis.ResultsResveratrol (100-150 μM) exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G0/G1-S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway.ConclusionsFor the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and activation of p53, suggesting its potential role as a chemotherapeutic agent.
Highlights
Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer
Overall our results demonstrate that resveratrol (i) suppresses insulin-like growth factors (IGFs)-1 receptor (IGF-1R) levels, downregulates Protein kinase B (Akt) and Wnt/β-catenin signaling; (ii) elevates levels of active Forkhead homolog like 1 (FKHRL1) and p27, and concomitantly suppresses cyclin D1 levels and (iii) activates p53 and suppresses sp1, suppressing cell cycle progression and elevating apoptosis in vitro even in the presence of free mitogenic insulin like growth factor-1 (IGF-1)
Our results demonstrated that resveratrol suppresses the colon cancer cell proliferation even when the cells are primed to proliferate with IGF-1
Summary
Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. A six-year study of 32,826 nurses, found that those with the highest levels of IGF-1 had a two-and-a-half times greater risk of colorectal cancer; another study of 14,916 male physicians concluded that men run the same risk [15,16]. This IGF system includes ligands, receptors, and ligand-binding proteins (IGFBPs). Over-nourishment and chronic hyperinsulinemia observed in obese conditions may deregulate colonocyte growth kinetics, as elevated insulin and suppressed IGFBP-1, and IGFBP-2 levels increase the pool of free or bioavailable IGF-1. The β-catenin/TCF-4 complex constitutes the master switch that regulates colonocyte proliferation [27]
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