ECE2018 Guided Posters Adrenal medulla and NETs (11 abstracts)
Targeted destruction of FSHR-positive cancer cells by a lytic Phor21-FSHb conjugate
Marcin Chruściel 1, , Joanna Stelmaszewska 3 , Milena Doroszko 1 , Donata Ponikwicka-Tyszko 2 , Jorma Toppari 1, , Sławomir Wołczynski 3 , Adam Ziecik 2 , Ilpo Huhtaniemi 1, & Nafis Rahman 1,
1University of Turku, Turku, Finland; 2Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland; 3Medical University of Bialystok, Białystok, Poland; 4Turku University Hospital, Turku, Finland; 5Imperial College London, London, UK.
Expression of the follicle-stimulating hormone receptor (FSHR) has been shown in gonads, gonadal tumors, and in endothelial tumor vessel cells of various cancers. We investigated the specificity and cytotoxicity of a fusion lytic peptide Phor21, conjugated to different FSHβ-chain fragments to ablate FSHR expressing cancer cells in vitro and in vivo. Cytotoxicity of 12 different Phor21-FSHβ conjugates was tested in HEK-293 cells, stably transfected with human FSHR cDNA (HEK293-FSHR) or mock-transfected HEK-293 cells used as FSHR-negative control cells. Phor21 linked to FSHβ33-53 fragment with cysteine (Cys) replaced by serine (Ser) (Phor21-FSHβ33-53C/S) displayed dose-dependently the highest specific cytotoxicity towards HEK293-FSHR cells vs. other compounds. Competitive studies with recombinant human FSH (rhFSH, 100 IU/l) significantly decreased the cytotoxicity of Phor21-FSHβ33-53C/S conjugate in HEK293-FSHR cells. In vivo Phor21-FSHβ33-53C/S treatment significantly inhibited the growth of HEK293-FSHR xenografts inducing necrosis. The efficacy of Phor21-FSHβ33-53C/S was enhanced by the GnRH antagonist cetrorelix (CTX) co-treatment. CTX alone displayed pro-apoptotic action. The growth of LNCaP cell xenografts, with previously reported FSHR-positive tumor vessel endothelial cells, was significantly inhibited by CTX, whereas Phor21-FSHβ33-53C/S showed no effect. We, therefore, revisited the expression of Fshr in LNCaP xenograft murine vessels. No Fshr transcripts in the endothelium of tumor vessel cells could be found. Our results emphasize the strong need to clarify the functional FSHR expression in the tumor vessel endothelial cells and different cancer cell lines. We proved the principle that the Phor21-FSHβ33-53C/S conjugate may provide a novel specific therapeutic lead into the targeted destruction of FSHR expressing cancer cells.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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