The hedgehog/Gli-1 signaling pathways is involved in the inhibitory effect of resveratrol on human colorectal cancer HCT116 cells

Document Type : Original Article


1 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China

2 Office of Development and Planning, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China


Objective(s): The study aimed to investigate the effects of resveratrol on colorectal cancer HCT116 cells, including cell viability, apoptosis, and migration, and the partial mechanisms focused on hedgehog/gli-1 signaling pathways.
Materials and Methods: We chose the appropriate time and concentration of recombinant human Sonic hedgehog (Shh) stimulation by cell viability. The proportion of cell apoptosis was detected by flow cytometry; HCT116 cell migration was measured by scratch test; the expression of Ptch, Smo, and Gli-1 was measured by Western blot analysis.
Results: Shh signaling increased HCT116 cell viability and migration, inhibited cell apoptosis, and upregulated the expression of Ptch, Smo, and Gli-1. Resveratrol obviously inhibited HCT116 cell viability and migration, promoted cell apoptosis, and suppressed the protein of Ptch, Smo, and Gli-1. Furthermore, the effects of resveratrol and Shh on human colorectal cancer HCT116 cells were in a dose- and time-dependent manner.
Conclusion: The inhibitory effect of resveratrol on HCT116 cells may be mediated by hedgehog/gli-1 signaling pathways.


1. Pallag A, Rosca E, ţiŢ DM, MuŢiu G, Bungău SG, Pop OL. Monitoring the effects of treatment in colon cancer cells using immunohistochemical and histoenzymatic techniques. Rom J Morphol Embryol 2015; 56:1103-1109.
2. Wong MC, Wong SH, Ng SC, Wu JC, Chan FK, Sung JJ. Targeted screening for colorectal cancer in high-risk individuals. Best Pract Res Clin Gastroenterol 2015; 29:941-951.
3. Thomas SA, Tomeh N,Theard S. Fluorouracil-induced hyperammonemia in a patient with colorectal cancer. Anticancer Res 2015; 35:6761-6763.
4. Li AM, Miao JH, Liu H, Ma YZ, Sun ZC. Drug-induced skin toxicity and clinical nursing of VitK cream on colorectal cancer patients. Pak J Pharm Sci 2015; 28:1499- 1503.
5. Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med 2013; 19:619-625.
6. Briscoe J, Thérond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 2013; 1:416-429.
7. Jia Y, Wang Y, Xie J. The Hedgehog pathway: role in cell differentiation, polarity and proliferation. Arch Toxicol 2015; 89:179-191.
8. Stecca B, Ruiz I Altaba A. Context-dependent regulation of the GLI code in cancer by Hedgehog and non-Hedgehog signals. J Mol Cell Biol 2010; 2:84–95.
9. Onishi H, Katano M. Hedgehog signaling pathway as a therapeutic target in various types of cancer. Cancer Sci 2011; 102:1756–1760.
10. Key TJ. Fruit and vegetables and cancer risk. Br J Cancer 2011; 104:6-11.
11. Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K. Clinical trials of resveratrol. Ann N Y Acad Sci 2011; 1215:161-169.
12. Frazzi R, Valli R, Tamagnini I, Casali B, Latruffe N, Merli F. Resveratrol- mediated apoptosis of hodgkin lymphoma cells involves SIRT1 inhibition and FOXO3a hyperacetylation. Int J Cancer 2013; 132:1013-1021.
13. Xie J, Bartels CM, Barton SW, Gu D. Targeting hedgehog signaling in cancer: research and clinical developments. Onco Targets Ther 2013; 6:1425–1435.
14. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, et al. Inhibition  of  the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009; 361:1164–1172.
15. Ruiz i Altaba A, Mas C, Stecca B. The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol 2007; 17:438–447.
16. Wallace VA. Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol 1999; 9:445-448.
17. Yang L, Xie G, Fan Q, Xie J. Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene 2010; 29:469-481.
18. Gu D, Liu H, Su GH, Zhang X, Chin-Sinex H, Hanenberg H, et al. Combining hedgehog signaling inhibition with focal irradiation on reduction of pancreatic cancer metastasis. Mol Cancer Ther 2013; 12:1038-1048.
19. Heller E, Hurchla MA, Xiang J, Su X, Chen S, Schneider J, et al. Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment. Cancer Res 2012; 72:897-907.
20. Hwang RF, Moore TT, Hattersley MM, Scarpitti M, Yang B, Devereaux E, et al. Inhibition of the hedgehog pathway targets the tumor-associated stroma in pancreatic cancer. Mol Cancer Res 2012; 10:1147-1157.
21. Javelaud D, Pierrat MJ, Mauviel A. Crosstalk between TGF-β and hedgehog signaling in cancer. FEBS Lett 2012; 586:2016-2025.
22. Joost S, Almada LL, Rohnalter V, Holz PS, Vrabel AM, Fernandez-Barrena MG, et al. GLI1 inhibition promotes epithelial-to-mesenchymal transition in pancreatic cancer cells. Cancer Res 2012; 72:88-99.
23. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 2004; 24:2783-840.
24. Khan A, Aljarbou AN, Aldebasi YH, Faisal SM, Khan MA. Resveratrol suppresses the proliferation of breast cancer cells by inhibiting fatty acid synthase signaling pathway. Cancer Epidemiol 2014; 38:765-772.
25. Singh CK, Ndiaye MA, Ahmad N. Resveratrol and cancer: Challenges for clinical translation. Biochim Biophys Acta 2015; 1852:1178-1185.
26. Empl MT, Albers M, Wang S, Steinberg P. The Resveratrol Tetramer r-Viniferin Induces a Cell Cycle Arrest Followed by Apoptosis in the Prostate Cancer Cell Line LNCaP. Phytother Res 2015; 29:1640-1645.