Abstract
BackgroundResveratrol (RES), an estrogen analog, is considered as a potential cancer chemo-preventive agent. However, it remains unclear how RES is transported into cells. In this study, we observed that Caveolin-1(CAV1) expression can increase the cytotoxic and pro-apoptotic activity of RES in a dose- and time-dependent manner both in vitro and in vivo in a Hepatocellular Carcinoma animal model.MethodsHigh performance liquid chromatography (HPLC) demonstrated that RES intra-cellular concentration is increased about 2-fold in cells stably expressing CAV1 or CAVM1 (a scaffolding domain (81-101AA)-defective CAV1 mutant) compared to the untransduced human Hepatoblastoma cell line (HepG2) or after transduction with the green fluorescent protein (GFP) control vector. The increased intra-cellular transport of RES was abolished in cells stably expressing CAVM2 (a cholesterol shuttle domain (143-156AA)-defective CAV1 mutant) or CAVRNAi. In order to further characterize CAV1-dependent RES transport, we synthesized RES-dansyl chloride derivatives as fluorescent probes to visualize the transport process, which demonstrated a distribution consistent with that of CAV1 in HepG2 cells.ResultsIn addition, RES endocytosis was not mediated by estrogen receptor (ER) α and β, as suggested by lack of competitive inhibition by estrogen or Tamoxifen. Pathway analysis showed that RES can up-regulate the expression of endogenous CAV1; this activates further the MAPK pathway and caspase-3 expression.DiscussionThis study provides novel insights about the role played by CAV1 in modulating cellular sensitivity to RES through enhancement of its internalization and trafficking.
Highlights
Resveratrol (RES), an estrogen analog, is considered as a potential cancer chemopreventive agent
Dose-and time-dependent cell death induced by RES in human hepatoblastoma carcinoma HepG2 cells To determine whether CAV1 is involved in the cytotoxic and pro-apoptotic activity of RES, HepG2 cells were treated with different doses of RES (0, 10, 30, 50, 100, 200 and 300 μmol/L)
HepG2 cells were treated with 200 μmol/L RES for 24, 48 and 72 h; cell growth inhibition increased in time in the control HepG2 cell lines from 55.45 ± 1.4, 68.91 ± 1.8, 78.83 ± 3.9 compared to baseline levels after 24, 48 and 72 h respectively
Summary
Resveratrol (RES), an estrogen analog, is considered as a potential cancer chemopreventive agent. RES can inhibit the growth of a variety of tumor cells in vitro and in animal models [7,8,9] through its anti-cancer properties including prevention, delay, and reversal of tumor initiation, promotion and progression. This is partly attributable to RES antioxidant activity and inhibitory effect on the hydroperoxidase activity of cyclooxygenase (Cox 1 and 2); RES can inhibit transcription factors such as NF-kB, apoptotic protease activating factors (Apaf-1), and AHR, growth of estrogen responsive cells and induce accumulation of p53 [10,11,12,13,14]. Most of the in vivo studies have failed to confirm the estrogen-like potential of RES
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