Caveolin-1 overexpression enhances androgen-dependent growth and proliferation in the mouse prostate

Bryant, Kelly G.; Camacho, Jeanette; Jasmin, Jean-François; Wang, Chenguang; Addya, Sankar; Casimiro, Mathew C.; Fortina, Paolo; Balasubramaniam, Sucharitha; Knudsen, Karen E.; Schwarting, Roland; Lisanti, Michael P.; Mercier, Isabelle Le

doi:10.1016/j.biocel.2011.04.019

Cited by 19 publications

(12 citation statements)

References 54 publications

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“…Serine 81 phosphorylation of AR is strongly associated with PCa growth and proliferation and induces AR transcriptional activity [22, 26]. Cav-1 increases AR nuclear translocation [11], while its overexpression induces AR phosphorylation on serine 210, which is associated with increased activation under androgen-stimulated conditions [27]. We found that Cav-1 induced the expression of ACC1 and FASN, even in the absence of AR, and in AR- PCa cell lines and that Cav-1 manipulation resulted in alteration of ACC1 and FASN RNA levels and palmitate synthesis.…”

Section: Discussionmentioning

confidence: 99%

Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer

et al. 2016

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Caveolin-1 (Cav-1) is overexpressed in aggressive and metastatic prostate cancer (PCa) and induces PCa cell proliferation. Androgens mediate lipid synthesis through acetyl-CoA carboxylase-1 (ACC1) and fatty acid synthase (FASN). We investigated the Cav-1-mediated lipid synthesis in the development of castration resistance, and identified novel therapeutic opportunities. Using the PBCre+;Ptenloxp/loxp;PBCav-1+ mouse model we found that Cav-1 induction increased cancer incidence and growth, and ACC1-FASN expression in intact and castrated mice. We demonstrated that Cav-1 regulated ACC1 and FASN expression in an AR-independent way and increased palmitate synthesis using western blot analysis, qRT-PCR and mass spectrometry in vitro. By using FASN siRNA and C-75, we found that FASN inhibition was more effective in Cav-1-overexpressing cells. This inhibition was abrogated by ACC1si RNA, revealing the role of malonyl-CoA, an ACC1 product, as a mediator of cytotoxicity. Cav-1 was associated with ACC1 in human tumors and ACC1, FASN, and Cav-1 expression were increased in metastatic PCa compared to primary tumors and normal prostate epithelium. Palmitoleate and oleate levels were higher in BMA from patients with metastatic PCa who responded poorly to abiraterone acetate. Our findings suggest that Cav-1 promotes hormone resistance through the upregulation of ACC1-FASN and lipid synthesis under androgen deprivation, suggesting that FASN inhibition could be used to treat PCa that demonstrates Cav-1 overexpression.

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Section: Discussionmentioning

confidence: 99%

Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer

et al. 2016

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“…Caution should also be taken when investigating AR-P in the literature as some of the phosphorylation sites are given different numbers, which can confuse the reader. For example, Ser210 is described as phosphorylated (Lin et al 2001b, McCall et al 2008, Shank et al 2008, Bryant et al 2011; however, when referring to the standard AR protein sequence (ANDR HUMAN, P10275), an arginine is found at this site, while in other studies, the same serine in question is referred to as Ser213 (Wen et al 2000, Nan et al 2003, Burgdorf et al 2004, Taneja et al 2005, Kim & Lee 2009, Lee 2009). In this review, the nomenclature used will correspond to the standard sequence to avoid such confusion.…”

Section: Serine Phosphorylationmentioning

confidence: 99%

“…Similarly, IGF1 stimulation in skeletal muscle cells results in increased AR protein and transcript levels and enhanced p-Ser213 (Kim & Lee 2009) via Akt (Lee 2009) to promote AR nuclear translocation in the absence of androgens (Kim & Lee 2009). Interestingly, overexpression of caveolin 1, a co-activator of AR, is associated with increased phosphorylation of Ser213 (Bryant et al 2011). A phosphospecific antibody has now been developed against p-Ser213, which revealed that the appearance of this modification in response to androgens depends on exactly which androgen is used.…”

Section: Ar-p Under Androgen-depleted Conditionsmentioning

confidence: 99%

Regulation of the androgen receptor by post-translational modifications

Coffey

Robson

2012

Journal of Endocrinology

121

100

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The androgen receptor (AR) is a key molecule in prostate cancer and Kennedy's disease. Understanding the regulatory mechanisms of this steroid receptor is important in the development of potential therapies for these diseases. One layer of AR regulation is provided by post-translational modifications including phosphorylation, acetylation, sumoylation, ubiquitination and methylation. While these modifications have mostly been studied as individual events, it is becoming clear that these modifications can functionally interact with each other in a signalling pathway. In this review, the effects of all modifications are described with a focus on interplay between them and the functional consequences for the AR.

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“…(6,22) In animal studies, development and progression of prostate tumors in Cav-1 -/-mice are significantly reduced, (23,24) and overexpression of Cav-1 in prostatic epithelial cells leads to prostatic hyperplasia. (25,26) Second, Cav-1 can be secreted by prostate cancer cells into the tumor microenvironment to promote growth and angiogenesis. (27)(28)(29) Secretion of Cav-1 was first reported from normal pancreatic acinar cells, (30) and it might be a unique mechanism adopted by prostate cancer cells to promote malignant progression.…”

Section: Introductionmentioning

confidence: 99%

Anti-caveolin-1 Antibodies As Anti-Prostate Cancer Therapeutics

et al. 2012

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Caveolae are critical cell surface structures important in coordinated cell signaling and endocytosis. One of the major proteins of caveolae is caveolin 1 (Cav-1). Cellular levels of Cav-1 are associated with cancer progression. In prostate cancer cells, levels of Cav-1 are positively correlated with tumor progression and metastasis. Cav-1 can be secreted by prostate cancer cells into the microenvironment and triggers proliferation and anti-apoptosis of the tumor and tumor endothelial cells. Clinical studies have shown increased serum Cav-1 levels in patients with poor prognosis. In tissue culture and animal model experiments, blocking secreted Cav-1 by polyclonal antibodies inhibits tumor cell growth. Cav-1 is therefore a potential therapeutic target for prostate cancer treatment. In this study, we used Cav-1 knock-out mice as hosts to produce monoclonal anti-Cav-1 antibodies. A total of 11 hybridoma cell lines were selected for their ability to produce antibodies that bound GST-Cav-1 but not GST on glutathione-coated ELISA plates. Further screening with ELISAs using GST-Cav-1 fragments on GSH-coated plates classified these antibodies into four groups: N1-31 with five antibodies binds the far Nterminus between amino acids 1 and 31; N32-80 with three antibodies binds between amino acids 32 and 80; CSD with two antibodies potentially bind the scaffolding domain (amino acids 80-101); and Cav-1-C with 1 antibody binds parts of the C-terminal half. Binding affinities (Kd) of these antibodies to soluble Cav-1 ranged from 10 -11 to 10 -8 M. Binding competition experiments revealed that these antibodies recognized a total of six different epitopes on Cav-1. Potency of these antibodies to neutralize Cav-1-mediated signaling pathways in cultured cells and in animal models will be tested. A selected monoclonal antibody will then be humanized and be further developed into a potential anti-prostate cancer therapeutic.

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Caveolin-1 overexpression enhances androgen-dependent growth and proliferation in the mouse prostate

Cited by 19 publications

References 54 publications

Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer

Caveolin-1 regulates hormone resistance through lipid synthesis, creating novel therapeutic opportunities for castration-resistant prostate cancer

Regulation of the androgen receptor by post-translational modifications

Anti-caveolin-1 Antibodies As Anti-Prostate Cancer Therapeutics

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