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

Abstract

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.

Endothelial Caveolin-1 regulates the radiation response of epithelial prostate tumors

“…Of note, recent investigations revealed that blocking the secreted Cav1 by polyclonal antibodies inhibited the growth of experimental prostate tumors in mice. 70 Nevertheless, the accelerated growth of the untreated prostate tumors in the Cav1-deficient background hints to a potential risk of treatment strategies targeting endothelial Cav1 for improving the radiation response in these tumors. Though increased tumor growth in Cav1 knockout mice is expected be rather a long-term effect of Cav1-deficiency, these observations make a careful validation of such treatment strategies with respect to adverse growth promoting effects absolutely necessary.…”

PTRF/cavin-1 neutralizes non-caveolar caveolin-1 microdomains in prostate cancer

“…4,6 Furthermore, anticaveolin-1 antibodies to neutralize circulating caveolin-1 have been suggested as potential therapy in prostate cancer. 7 As caveolin-1 is an essential structural component of plasma membrane caveolae, cholesterol-rich-invaginated pits at the plasma membrane, 8 it has been assumed that caveolin-1 in prostate cancer cells forms caveolae. However, we recently demonstrated that the caveolin-1-positive prostate cancer cell line PC-3 lacks caveolae because of the absence of an essential co-factor cavin-1 (also known as PTRF; polymerase I and transcript release factor).…”

Deregulation of E-cadherin, β-catenin, APC and Caveolin-1 expression occurs in canine prostate cancer and metastatic processes

“…Immunohistochemistry revealed granular CAV-1 and PC cytoplasmic staining with lower Gleason scores (grade 6) and showed lower protein expression than in higher Gleason score PC. In humans, CAV-1 expression is positively correlated with high-grade Gleason scores, early recurrence time and therapeutic resistance (Karam et al, 2007;Kuo et al, 2012;Quest et al, 2013).…”