Resveratrol Suppresses IGF-1 Induced Human Colon Cancer Cell Proliferation and Elevates Apoptosis via Suppression of IGF-1R/Wnt and Activation of p53 Signaling Pathways

BMC Cancer. 2010 May 26;10:238. doi: 10.1186/1471-2407-10-238.

Abstract

Background: Obesity 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.

Methods: We 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.

Results: Resveratrol (100-150 microM) 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.

Conclusions: For 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects*
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27
  • Dose-Response Relationship, Drug
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism
  • HT29 Cells
  • Humans
  • Insulin-Like Growth Factor I / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Resveratrol
  • Signal Transduction / drug effects*
  • Stilbenes / pharmacology*
  • Time Factors
  • Tumor Suppressor Protein p53 / metabolism*
  • Wnt Proteins / metabolism*

Substances

  • Antineoplastic Agents, Phytogenic
  • CCND1 protein, human
  • CDKN1B protein, human
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • Stilbenes
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Wnt Proteins
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • Resveratrol