Resveratrol suppresses colon cancer growth by targeting the AKT/STAT3 signaling pathway

Abstract

colon cancer is a common type of cancer worldwide and accounts for a significant number of cancer-related deaths. Although surgical techniques and treatment strategies for colon cancer have advanced over the past two decades, the prognosis has not improved considerably. Resveratrol, a natural stilbene compound, possesses antioxidant, cardioprotective and anticancer properties. However, the role of resveratrol in colon cancer has not been fully elucidated. The present study demonstrated that resveratrol inhibited cell proliferation and colony growth in DLD1 and HCT15 colon cancer cells, but did not affect normal colon epithelial cells. The resveratrol-mediated inhibition of cell proliferation correlated with an induction of apoptosis and with G 1 phase cell cycle arrest in colon cancer cells. Additionally, resveratrol treatment decreased the protein expression levels of cyclin D1, cyclin E2 and BCL2 apoptosis regulator, while it increased BCL2 associated X and tumor protein p53, all of which are involved in the regulation of cell cycle and apoptosis. Notably, the results obtained from in silico computational screening identified AKT serine/threonine kinase 1 (AKT1) and AKT2 as novel targets of resveratrol.Computational docking suggested that there are three or four possible hydrogen bonds in the active pocket of AKT1 and AKT2 that contribute to the mode of action of resveratrol. The present study confirmed that resveratrol bound to AKT1 and AKT2 with a pull-down assay. Furthermore, knockdown of AKT1 and AKT2 inhibited cell proliferation and colony growth, by attenuating cell cycle progression and increasing apoptosis in colon cancer cells, effects that were similar to those caused by resveratrol treatment. Taken together, the present results suggest that the targeting effects of resveratrol to AKT1 and AKT2 may be a potent strategy for chemoprevention or therapy for colon cancer.

Resveratrol and Its Nanoformulation Attenuate Growth and the Angiogenesis of Xenograft and Orthotopic Colon Cancer Models

“…Resveratrol is considered to be a promising anticancer drug for chemoprevention or therapy for colon cancer, targeting numerous cellular molecules, such as AKT serine/threonine kinase 1 (AKT1), AKT2 [19], and AKT/GSK-3β/Snail signaling pathway [20], and increasing ROS production [21]. In the current study, RSV at a dose of 6 µ g/implant significantly reduced the tumor weight of s.c. (subcutaneously)-implanted COLO205-luc in athymic mice.…”

Resveratrol suppresses melanoma growth by promoting autophagy through inhibiting the PI3K/AKT/mTOR signaling pathway

“…In summary, these data suggested that RV retards melanoma growth in an autophagy-dependent manner through the inhibition of PI3K/AKT/mTOR signaling. Previous studies have similarly reported that RV can potentially prevent various malignancies through inhibiting cellular proliferation and regulating autophagy (22)(23)(24). In a study by Lei et al (25), RV decreased proliferation, enhanced cellular differentiation and improved melanin generation in HT-144 melanoma cells through inhibiting the mitogen-activated protein kinase kinase/ERK kinase pathway.…”

Resveratrol Suppresses the Growth and Metastatic Potential of Cervical Cancer through Inhibiting STAT3Tyr705 Phosphorylation

“…Studies have shown that resveratrol inhibits IL-6induced transcriptional activity of STAT3 in human prostate cancer LNCaP-FGC cells (18), and STAT3 axis in primary glioblastoma tumor initiating cells (19). Inhibition of STAT3 signaling plays a critical role in resveratrol-induced suppression of several types of cancer, including ovarian cancer (20,21), pancreatic cancer cells (22), head and neck tumor cells (23), osteosarcoma (24), colorectal cancer (25), colon cancer (26). In these types of cancers, it has been shown that resveratrol inhibits STAT3 Tyr705 phosphorylation (22)(23)(24)(25)(26) and STAT3 S727 phosphorylation (23,25).…”

“…Inhibition of STAT3 signaling plays a critical role in resveratrol-induced suppression of several types of cancer, including ovarian cancer (20,21), pancreatic cancer cells (22), head and neck tumor cells (23), osteosarcoma (24), colorectal cancer (25), colon cancer (26). In these types of cancers, it has been shown that resveratrol inhibits STAT3 Tyr705 phosphorylation (22)(23)(24)(25)(26) and STAT3 S727 phosphorylation (23,25). Zhang et al showed that STAT3 signaling is more critical for cervical cancer cells and is the major target of resveratrol because selective inhibition of STAT3 rather than Wnt or Notch activation commits SiHa and Hela cells to apoptosis (27).…”