Targeted destruction of follicle stimulating hormone receptor-positive cancer cells in vitro and in vivo by a lytic peptide Phor21-FSHβ conjugate

Abstract

<p>Background<br>Extragonadal follicle-stimulating hormone (FSH) receptor (FSHR) expression in various cancers and their<br>endothelial vessel cells has highlighted novel opportunities for targeted FSHR therapy.<br>Methods<br>We investigated the specificity/cytotoxicity of Phor21 fusion lytic peptide, conjugated to 12 different FSHβchain fragments to ablate FSHR-expressing cancer cells in vitro and in vivo. Additionally, the use of the gonadotropinreleasing hormone (GnRH) antagonist cetrorelix (CTX) alone or with the Phor21-FSHβ33-53 C/S conjugate for anticancer therapy was analyzed.<br>Results<br>Phor21 linked to the FSHβ33–53 fragment with cysteine (Cys) replaced by serine (Ser) (Phor21-<br>FSHβ33-53 C/S) demonstrated the highest specific cytotoxicity towards FSHR possessing cancer cells vs. other compounds. Recombinant human FSH treatment significantly decreased the cytotoxicity of Phor21-FSHβ33-53 C/S conjugate in FSHR-positive cancer cells. Phor21-FSHβ33-53 C/S (further addressed as Phor21-FSHβ) treatment in vivo significantly inhibited the growth of FSHR-positive cancer xenografts, resulting in necrosis. The efficacy of the Phor21-FSHβ was enhanced by co-treatment with the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix (CTX). CTX alone exerted pro-apoptotic effects. CTX significantly inhibited the growth of prostate cancer LNCaP cell xenografts. Although FSHR-positive tumor vessel endothelial cells were previously reported in LNCaP cell xenografts, we were unable to reproduce FSHR expression. Consequently, Phor21-FSHβ had no effect on tumor destruction because of the lack of Fshr transcripts in the endothelium of these tumor vessel cells.<br>Conclusion<br>This novel functional evidence shows that any cancer cell expressing FSHR can be specifically targeted<br>and destroyed by the conjugated lytic peptide Phor21-FSHβ33–53 (Phor21-FSHβ). FSHR expression was not detected in the tumor vessel endothelial cells, which needs further re-evaluation.<br></p>