Resveratrol inhibits proliferation and migration through SIRT1 mediated post-translational modification of PI3K/AKT signaling in hepatocellular carcinoma cells

Abstract

Resveratrol (RES), a polyphenolic compound present in grapes and red wine, has potential anticancer properties. The present study aimed to examine the effects of resveratrol and its underlying mechanism on hepatocellular carcinoma (HCC) cell lines HepG2, Bel-7402 and SMMC-7721. It was demonstrated that resveratrol inhibited the viability and proliferation of HCC cells assessed by MTT and EdU assays. TUNEL assay revealed that resveratrol induced cell apoptosis by increasing HCC apoptosis rate from 3±0.78% to 16±1.12% with upregulation of B-cell lymphoma (Bcl)-2 associated X, apoptosis regulator and cleaved-poly (ADP-Ribose) polymerase 1 (PARP), and downregulation of Bcl-2, caspase-3, caspase-7 and PARP. As a sirtuin (SIRT) 1 activator, resveratrol elevated SIRT1 protein expression and its enzyme activity and decreased expression levels of phosphorylated (p)-phosphoinositide-3-kinase (PI3K), p-AKT Serine/Threonine Kinase 1 (AKT), and its downstream target p-Forkhead Box O3a in HepG2 cells. Furthermore, inhibition of SIRT1 enzymatic activity by EX527 resulted in increased phosphorylation levels of PI3K and AKT. This demonstrated that resveratrol inhibited the PI3K/AKT pathway by SIRT1 activation. In addition to inhibition of cancer cell migration, tumor suppressor gene DLC1 Rho GTPase activating protein level was upregulated and its phosphorylation was enhanced by AKT with resveratrol treatment. These findings suggested that resveratrol inhibits proliferation and migration through SIRT1 mediated post-translational modification of PI3K/AKT pathway in HCC cells.

Resveratrol promotes sensitization to Doxorubicin by inhibiting epithelial‐mesenchymal transition and modulating SIRT1/β‐catenin signaling pathway in breast cancer

“…Based on this, we detected that RES downregulated the expression of β‐catenin time‐ and dose‐dependently in MCF7/ADR cells. RES is a well‐known activator of SIRT1 which was reported to inhibit proliferation and migration through SIRT1‐mediated posttranslational modification of PI3K/Akt signaling in hepatocellular carcinoma cells . Another report revealed that SIRT1 promotes EMT in colorectal cancer by regulating Fra‐1 .…”

miR‑202 suppresses prostate cancer growth and metastasis by targeting PIK3CA

“…PI3K/AKT pathway is a vital regulator in cell proliferation, metastasis and apoptosis by modulating downstream targets, such as mammalian target of rapamycin (mTOR) and Cyclin-dependent kinase inhibitors (27). Increasing evidence shows that PI3K/AKT pathway is closely related with the tumorigenesis, such as breast cancer (28), hepatocellular carcinoma (29) and PC (30). Dysregulated expression of PIK3CA led to abnormal activation of PI3K/AKP pathway and consequently development of cancers.…”

Nrf2–Keap1 pathway–mediated effects of resveratrol on oxidative stress and apoptosis in hydrogen peroxide–treated rheumatoid arthritis fibroblast‐like synoviocytes

“…Resveratrol (Res) is a natural phenolic compound whose anti‐inflammatory, anticancer, and antioxidant effects have been confirmed by the medical community . According to the literature reports, Michael acceptors can react with cysteine thiolate (soft base) groups in Kelch‐like ECH–related protein 1 (Keap1) and consequently induce nuclear factor erythroid 2–related factor 2 (Nrf2) accumulation that leads to upregulated expression of antioxidant responsive element (ARE)‐mediated antioxidative and cytoprotective enzymes.…”