Caveolin-I enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model

Hui Ling Yang, Wei Qiong Chen, Xuan Cao, Andrea Worschech, Li Fen Du, Wei Yi Fang, Yang Yan Xu, David F. Stroncek, Xin Li, Ena Wang, Francesco M. Marincola

Research output: Contribution to journalArticle

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Abstract

Background: Resveratrol (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. Methods: High 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. Results: In 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. Discussion: This study provides novel insights about the role played by CAV1 in modulating cellular sensitivity to RES through enhancement of its internalization and trafficking.

Original languageEnglish
Article number22
JournalJournal of Translational Medicine
Volume7
DOIs
Publication statusPublished - 25 Mar 2009
Externally publishedYes

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Caveolins
Caveolin 1
Cytotoxicity
Hepatocellular Carcinoma
resveratrol
Estradiol Congeners
Hepatoblastoma
Hep G2 Cells
High performance liquid chromatography
Tamoxifen
Endocytosis
Green Fluorescent Proteins
Fluorescent Dyes
Caspase 3
Estrogen Receptors
Estrogens
Animals
Up-Regulation
Animal Models
Cholesterol

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yang, H. L., Chen, W. Q., Cao, X., Worschech, A., Du, L. F., Fang, W. Y., ... Marincola, F. M. (2009). Caveolin-I enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model. Journal of Translational Medicine, 7, [22]. https://doi.org/10.1186/1479-5876-7-22

Caveolin-I enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model. / Yang, Hui Ling; Chen, Wei Qiong; Cao, Xuan; Worschech, Andrea; Du, Li Fen; Fang, Wei Yi; Xu, Yang Yan; Stroncek, David F.; Li, Xin; Wang, Ena; Marincola, Francesco M.

In: Journal of Translational Medicine, Vol. 7, 22, 25.03.2009.

Research output: Contribution to journalArticle

Yang, HL, Chen, WQ, Cao, X, Worschech, A, Du, LF, Fang, WY, Xu, YY, Stroncek, DF, Li, X, Wang, E & Marincola, FM 2009, 'Caveolin-I enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model', Journal of Translational Medicine, vol. 7, 22. https://doi.org/10.1186/1479-5876-7-22
Yang, Hui Ling ; Chen, Wei Qiong ; Cao, Xuan ; Worschech, Andrea ; Du, Li Fen ; Fang, Wei Yi ; Xu, Yang Yan ; Stroncek, David F. ; Li, Xin ; Wang, Ena ; Marincola, Francesco M. / Caveolin-I enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model. In: Journal of Translational Medicine. 2009 ; Vol. 7.
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abstract = "Background: Resveratrol (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. Methods: High 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. Results: In 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. Discussion: This study provides novel insights about the role played by CAV1 in modulating cellular sensitivity to RES through enhancement of its internalization and trafficking.",
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AU - Du, Li Fen

AU - Fang, Wei Yi

AU - Xu, Yang Yan

AU - Stroncek, David F.

AU - Li, Xin

AU - Wang, Ena

AU - Marincola, Francesco M.

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