Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

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

Authors: Jairam Vanamala, Lavanya Reddivari, Sridhar Radhakrishnan, Chris Tarver

Published in: BMC Cancer | Issue 1/2010

Login to get access

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 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.

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.
Appendix
Available only for authorised users
Literature
1.
Flegal KM, Carroll MD, Ogden CL, Johnson CL: Prevalence and trends in obesity among US adults, 1999-2000. JAMA. 2002, 288: 1723-1727. 10.1001/jama.288.14.1723.CrossRefPubMed
2.
Caan BJ, Coates AO, Slattery ML, Potter JD, Quesenberry CP, Edwards SM: Body size and the risk of colon cancer in a large case-control study. Int J Obes Relat Metab Disord. 1998, 22: 178-184. 10.1038/sj.ijo.0800561.CrossRefPubMed
3.
Ford ES: Body mass index and colon cancer in a national sample of adult US men and women. Am J Epidemiol. 1999, 150: 390-398.CrossRefPubMed
4.
Frezza EE, Wachtel MS, Chiriva-Internati M: Influence of obesity on the risk of developing colon cancer. Gut. 2006, 55: 285-291. 10.1136/gut.2005.073163.CrossRefPubMedPubMedCentral
5.
Giacosa A, Franceschi S, La Vecchia C, Favero A, Andreatta R: Energy intake, overweight, physical exercise and colorectal cancer risk. Eur J Cancer Prev. 1999, 8 (Suppl 1): S53-60.PubMed
6.
Kono S, Handa K, Hayabuchi H, Kiyohara C, Inoue H, Marugame T, Shinomiya S, Hamada H, Onuma K, Koga H: Obesity, weight gain and risk of colon adenomas in Japanese men. Jpn J Cancer Res. 1999, 90: 805-811.CrossRefPubMed
7.
Murphy TK, Calle EE, Rodriguez C, Kahn HS, Thun MJ: Body mass index and colon cancer mortality in a large prospective study. Am J Epidemiol. 2000, 152: 847-854. 10.1093/aje/152.9.847.CrossRefPubMed
8.
Shike M: Body weight and colon cancer. Am J Clin Nutr. 1996, 63: 442S-444S.PubMed
9.
Vainio H, Bianchini F, (Eds): Weight Control and Physical Activity. 2002, Lyon, France: IARC Press
10.
11.
Grady WM, Carethers JM: Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology. 2008, 135: 1079-1099. 10.1053/j.gastro.2008.07.076.CrossRefPubMedPubMedCentral
12.
Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M: Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008, 371: 569-578. 10.1016/S0140-6736(08)60269-X.CrossRefPubMed
13.
Trayhurn P, Wood IS: Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans. 2005, 33: 1078-1081. 10.1042/BST20051078.CrossRefPubMed
14.
LeRoith D, Roberts CT: The insulin-like growth factor system and cancer. Cancer Lett. 2003, 195: 127-137.CrossRefPubMed
15.
Wei EK, Ma J, Pollak MN, Rifai N, Fuchs CS, Hankinson SE, Giovannucci E: A prospective study of C-peptide, insulin-like growth factor-I, insulin-like growth factor binding protein-1, and the risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev. 2005, 14: 850-855. 10.1158/1055-9965.EPI-04-0661.CrossRefPubMed
16.
Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, Stampfer MJ: Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst. 1999, 91: 620-625. 10.1093/jnci/91.7.620.CrossRefPubMed
17.
Vanamala J, Tarver CC, Murano PS: Obesity-enhanced colon cancer: functional food compounds and their mechanisms of action. Curr Cancer Drug Targets. 2008, 8: 611-633. 10.2174/156800908786241087.CrossRefPubMed
18.
Ahmed RL, Thomas W, Schmitz KH: Interactions between insulin, body fat, and insulin-like growth factor axis proteins. Cancer Epidemiol Biomarkers Prev. 2007, 16: 593-597. 10.1158/1055-9965.EPI-06-0775.CrossRefPubMed
19.
Frystyk J: Free insulin-like growth factors -- measurements and relationships to growth hormone secretion and glucose homeostasis. Growth Horm IGF Res. 2004, 14: 337-375. 10.1016/j.ghir.2004.06.001.CrossRefPubMed
20.
Davies M, Gupta S, Goldspink G, Winslet M: The insulin-like growth factor system and colorectal cancer: clinical and experimental evidence. Int J Colorectal Dis. 2006, 21: 201-208. 10.1007/s00384-005-0776-8.CrossRefPubMed
21.
Liang J, Slingerland JM: Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle. 2003, 2: 339-345.CrossRefPubMed
22.
Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB: Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005, 4: 988-1004. 10.1038/nrd1902.CrossRefPubMed
23.
Desbois-Mouthon C, Cadoret A, Blivet-Van Eggelpoel MJ, Bertrand F, Cherqui G, Perret C, Capeau J: Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. Oncogene. 2001, 20: 252-259. 10.1038/sj.onc.1204064.CrossRefPubMed
24.
Polakis P: The many ways of Wnt in cancer. Curr Opin Genet Dev. 2007, 17: 45-51. 10.1016/j.gde.2006.12.007.CrossRefPubMed
25.
Sanders LM, Henderson CE, Hong MY, Barhoumi R, Burghardt RC, Wang N, Spinka CM, Carroll RJ, Turner ND, Chapkin RS, Lupton JR: An increase in reactive oxygen species by dietary fish oil coupled with the attenuation of antioxidant defenses by dietary pectin enhances rat colonocyte apoptosis. J Nutr. 2004, 134: 3233-3238.PubMed
26.
Smith K, Bui TD, Poulsom R, Kaklamanis L, Williams G, Harris AL: Up-regulation of macrophage wnt gene expression in adenoma-carcinoma progression of human colorectal cancer. Br J Cancer. 1999, 81: 496-502. 10.1038/sj.bjc.6690721.CrossRefPubMedPubMedCentral
27.
Wetering van de M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, Horn van der K, Batlle E, Coudreuse D, Haramis AP, et al: The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell. 2002, 111: 241-250. 10.1016/S0092-8674(02)01014-0.CrossRefPubMed
28.
Banerjee S, Bueso-Ramos C, Aggarwal BB: Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 2002, 62: 4945-4954.PubMed
29.
Hope C, Planutis K, Planutiene M, Moyer MP, Johal KS, Woo J, Santoso C, Hanson JA, Holcombe RF: Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: implications for colon cancer prevention. Mol Nutr Food Res. 2008, 52 (Suppl 1): S52-61.PubMedPubMedCentral
30.
Gescher AJ, Steward WP: Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum. Cancer Epidemiol Biomarkers Prev. 2003, 12: 953-957.PubMed
31.
Aziz MH, Nihal M, Fu VX, Jarrard DF, Ahmad N: Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3'-kinase/Akt pathway and Bcl-2 family proteins. Mol Cancer Ther. 2006, 5: 1335-1341. 10.1158/1535-7163.MCT-05-0526.CrossRefPubMed
32.
Sexton E, Van Themsche C, LeBlanc K, Parent S, Lemoine P, Asselin E: Resveratrol interferes with AKT activity and triggers apoptosis in human uterine cancer cells. Mol Cancer. 2006, 5: 45-10.1186/1476-4598-5-45.CrossRefPubMedPubMedCentral
33.
34.
Alkhalaf M: Resveratrol-induced apoptosis is associated with activation of p53 and inhibition of protein translation in T47D human breast cancer cells. Pharmacology. 2007, 80: 134-143. 10.1159/000103253.CrossRefPubMed
35.
Shieh SY, Ikeda M, Taya Y, Prives C: DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell. 1997, 91: 325-334. 10.1016/S0092-8674(00)80416-X.CrossRefPubMed
36.
Nahor I, Abramovitch S, Engeland K, Werner H: The p53-family members p63 and p73 inhibit insulin-like growth factor-I receptor gene expression in colon cancer cells. Growth Horm IGF Res. 2005, 15: 388-396. 10.1016/j.ghir.2005.07.005.CrossRefPubMed
37.
Werner H, Karnieli E, Rauscher FJ, LeRoith D: Wild-type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene. Proc Natl Acad Sci USA. 1996, 93: 8318-8323. 10.1073/pnas.93.16.8318.CrossRefPubMedPubMedCentral
38.
Ohlsson C, Kley N, Werner H, LeRoith D: p53 regulates insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced tyrosine phosphorylation in an osteosarcoma cell line: interaction between p53 and Sp1. Endocrinology. 1998, 139: 1101-1107. 10.1210/en.139.3.1101.CrossRefPubMed
39.
Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, et al: Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006, 444: 337-342. 10.1038/nature05354.CrossRefPubMed
40.
Fang J, Zhou Q, Shi XL, Jiang BH: Luteolin inhibits insulin-like growth factor 1 receptor signaling in prostate cancer cells. Carcinogenesis. 2007, 28: 713-723. 10.1093/carcin/bgl189.CrossRefPubMed
41.
Vanamala J, Leonardi T, Patil BS, Taddeo SS, Murphy ME, Pike LM, Chapkin RS, Lupton JR, Turner ND: Suppression of colon carcinogenesis by bioactive compounds in grapefruit. Carcinogenesis. 2006, 27: 1257-1265. 10.1093/carcin/bgi318.CrossRefPubMed
42.
Kaur M, Singh RP, Gu M, Agarwal R, Agarwal C: Grape seed extract inhibits in vitro and in vivo growth of human colorectal carcinoma cells. Clin Cancer Res. 2006, 12: 6194-6202. 10.1158/1078-0432.CCR-06-1465.CrossRefPubMed
43.
Rodrigues NR, Rowan A, Smith ME, Kerr IB, Bodmer WF, Gannon JV, Lane DP: p53 mutations in colorectal cancer. Proc Natl Acad Sci USA. 1990, 87: 7555-7559. 10.1073/pnas.87.19.7555.CrossRefPubMedPubMedCentral
44.
Guo Y, Harwalkar J, Stacey DW, Hitomi M: Destabilization of cyclin D1 message plays a critical role in cell cycle exit upon mitogen withdrawal. Oncogene. 2005, 24: 1032-1042. 10.1038/sj.onc.1208299.CrossRefPubMed
45.
Shahrabani-Gargir L, Pandita TK, Werner H: Ataxia-telangiectasia mutated gene controls insulin-like growth factor I receptor gene expression in a deoxyribonucleic acid damage response pathway via mechanisms involving zinc-finger transcription factors Sp1 and WT1. Endocrinology. 2004, 145: 5679-5687. 10.1210/en.2004-0613.CrossRefPubMed
46.
Moll UM, Petrenko O: The MDM2-p53 interaction. Mol Cancer Res. 2003, 1: 1001-1008.PubMed
47.
Hilmi C, Larribere L, Deckert M, Rocchi S, Giuliano S, Bille K, Ortonne JP, Ballotti R, Bertolotto C: Involvement of FKHRL1 in melanoma cell survival and death. Pigment Cell Melanoma Res. 2008, 21: 139-146. 10.1111/j.1755-148X.2008.00440.x.CrossRefPubMed
48.
Reddivari L, Vanamala J, Chintharlapalli S, Safe SH, Miller JC: Anthocyanin fraction from potato extracts is cytotoxic to prostate cancer cells through activation of caspase-dependent and caspase-independent pathways. Carcinogenesis. 2007, 28: 2227-2235. 10.1093/carcin/bgm117.CrossRefPubMed
49.
Vanamala J, Cobb G, Turner ND, Lupton JR, Yoo KS, Pike LM, Patil BS: Bioactive compounds of grapefruit (Citrus paradisi Cv. Rio Red) respond differently to postharvest irradiation, storage, and freeze drying. J Agric Food Chem. 2005, 53: 3980-3985. 10.1021/jf048167p.CrossRefPubMed
50.
Vanamala J, Glagolenko A, Yang P, Carroll RJ, Murphy ME, Newman RA, Ford JR, Braby LA, Chapkin RS, Turner ND, Lupton JR: Dietary fish oil and pectin enhance colonocyte apoptosis in part through suppression of PPARdelta/PGE2 and elevation of PGE3. Carcinogenesis. 2008, 29: 790-796. 10.1093/carcin/bgm256.CrossRefPubMed
51.
Dupont J, Pierre A, Froment P, Moreau C: The insulin-like growth factor axis in cell cycle progression. Horm Metab Res. 2003, 35: 740-750. 10.1055/s-2004-814162.CrossRefPubMed
52.
Laurino L, Wang XX, de la Houssaye BA, Sosa L, Dupraz S, Caceres A, Pfenninger KH, Quiroga S: PI3K activation by IGF-1 is essential for the regulation of membrane expansion at the nerve growth cone. J Cell Sci. 2005, 118: 3653-3662. 10.1242/jcs.02490.CrossRefPubMed
53.
Alao JP, Gamble SC, Stavropoulou AV, Pomeranz KM, Lam EW, Coombes RC, Vigushin DM: The cyclin D1 proto-oncogene is sequestered in the cytoplasm of mammalian cancer cell lines. Mol Cancer. 2006, 5: 7-10.1186/1476-4598-5-7.CrossRefPubMedPubMedCentral
54.
Zheng WH, Kar S, Quirion R: Insulin-like growth factor-1-induced phosphorylation of transcription factor FKHRL1 is mediated by phosphatidylinositol 3-kinase/Akt kinase and role of this pathway in insulin-like growth factor-1-induced survival of cultured hippocampal neurons. Mol Pharmacol. 2002, 62: 225-233. 10.1124/mol.62.2.225.CrossRefPubMed
55.
Biggs WH, Meisenhelder J, Hunter T, Cavenee WK, Arden KC: Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci USA. 1999, 96: 7421-7426. 10.1073/pnas.96.13.7421.CrossRefPubMedPubMedCentral
56.
Komatsu N, Watanabe T, Uchida M, Mori M, Kirito K, Kikuchi S, Liu Q, Tauchi T, Miyazawa K, Endo H, et al: A member of Forkhead transcription factor FKHRL1 is a downstream effector of STI571-induced cell cycle arrest in BCR-ABL-expressing cells. J Biol Chem. 2003, 278: 6411-6419. 10.1074/jbc.M211562200.CrossRefPubMed
57.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999, 96: 857-868. 10.1016/S0092-8674(00)80595-4.CrossRefPubMed
58.
You H, Jang Y, You-Ten AI, Okada H, Liepa J, Wakeham A, Zaugg K, Mak TW: p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. Proc Natl Acad Sci USA. 2004, 101: 14057-14062. 10.1073/pnas.0406286101.CrossRefPubMedPubMedCentral
59.
60.
Zheng WH, Kar S, Quirion R: Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells. J Biol Chem. 2000, 275: 39152-39158. 10.1074/jbc.M002417200.CrossRefPubMed
61.
Park KW, Kim DH, You HJ, Sir JJ, Jeon SI, Youn SW, Yang HM, Skurk C, Park YB, Walsh K, Kim HS: Activated forkhead transcription factor inhibits neointimal hyperplasia after angioplasty through induction of p27. Arterioscler Thromb Vasc Biol. 2005, 25: 742-747. 10.1161/01.ATV.0000156288.70849.26.CrossRefPubMed
62.
Tessitore L, Davit A, Sarotto I, Caderni G: Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression. Carcinogenesis. 2000, 21: 1619-1622. 10.1093/carcin/21.8.1619.CrossRefPubMed
63.
Li ZG, Hong T, Shimada Y, Komoto I, Kawabe A, Ding Y, Kaganoi J, Hashimoto Y, Imamura M: Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol. Carcinogenesis. 2002, 23: 1531-1536. 10.1093/carcin/23.9.1531.CrossRefPubMed
64.
Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 2006, 127: 469-480. 10.1016/j.cell.2006.10.018.CrossRefPubMed
Metadata
Title
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
Authors
Jairam Vanamala
Lavanya Reddivari
Sridhar Radhakrishnan
Chris Tarver
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-238

Other articles of this Issue 1/2010

BMC Cancer 1/2010 Go to the issue

Research article

Prognostic relevance of Bmi-1 expression and autoantibodies in esophageal squamous cell carcinoma

Research article

Characterization of ductal and lobular breast carcinomas using novel prolactin receptor isoform specific antibodies

Research article

4β-Hydroxywithanolide E from Physalis peruviana (golden berry) inhibits growth of human lung cancer cells through DNA damage, apoptosis and G2/M arrest

Research article

Extracerebral metastases determine the outcome of patients with brain metastases from renal cell carcinoma

Research article

Transcriptional profiling of ErbB signalling in mammary luminal epithelial cells - interplay of ErbB and IGF1 signalling through IGFBP3 regulation

Research article

High number of CD45RO+ tumor infiltrating lymphocytes is an independent prognostic factor in non-metastasized (stage I-IIA) esophageal adenocarcinoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits