IDDF2022-ABS-0089 Resveratrol suppresses colorectal cancer by down-regulation of notch signaling pathway activity

Background

Numerous evidence reveals that dysregulation of the Notch signaling pathway is associated with the pathogenesis of various malignancies, including colorectal cancer (CRC). Resveratrol, 3,5,4'-Trihydroxystilbene, is a phytoalexin abundant in the Vitis and some medicinal plants, particularly Polygonum Cuspidatum. Resveratrol possesses powerful activities against CRC, with the underlying mechanisms to be illuminated. The present study investigated the potencies of resveratrol on CRC and deciphered the underlying mechanisms in the context of the Notch signaling cascade.

Methods

The effects of resveratrol on the proliferation, migration, apoptosis, cell cycle and Notch signaling pathway activity of HCT116 CRC cells were examined in vitro. In subcutaneous HCT116 xenograft tumor on BALB/c nude mice, the efficacies of resveratrol on the carcinogenesis, pathological profile, apoptosis and Notch signaling axis were determined in vivo as well.

Results

Resveratrol inhibited the proliferation and migration of HCT116 cells in a concentration-dependent manner. Flow cytometric analysis and Hoechst 33342/Propidium Iodide staining indicated that resveratrol induced apoptosis of HCT116 cells and arrested cell cycle, accompanied by attenuated mRNA and protein levels of anti-apoptotic BCL-2 (B-cell lymphoma 2), and heightened those of pro-apoptotic BAX (BCL-2-associated X) and caspase-3 in HCT116 cells. Also, resveratrol drastically diminished the mRNA and protein expressions of the players in the Notch signaling pathway, such as Jagged1, Notch1, DLL1 (delta-like ligand 1), ADAM17 (a disintegrin and metallopeptidase domain 17), NICD1 (Notch1 intracellular domain), Hes1 (hairy and enhancer of split 1), c-Myc and cyclin D1 in HCT116 cells. HCT116 xenograft tumor assay showed that resveratrol substantially hindered tumor growth and ameliorated pathological manifestation. TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay suggested that resveratrol caused the apoptosis of CRC tissue, with increased mRNA and protein levels of BAX and caspase-3, and decreased those of BCL-2. In addition, resveratrol sharply reduced the mRNA and protein expressions of the molecules in the Notch signaling pathway, such as Jagged1, Notch1, DLL1, ADAM17, NICD1, Hes1, c-Myc and cyclin D1 in CRC tissue.

Conclusions

Resveratrol potentially suppresses the growth and metastasis, and induces the apoptosis of CRC by down-regulation of Notch signaling pathway activity.