A novel targeted therapy of Leydig and granulosa cell tumors through the luteinizing hormone receptor using a hecate-chorionic gonadotropin beta conjugate in transgenic mice.
We investigated the antitumoral efficacy, endocrine consequences, and molecular mechanisms underlying cell death induced by the Hecate-chorionic gonadotropin (CG)beta conjugate, a fusion protein of a 23-amino acid lytic peptide Hecate with a 15-amino acid (81-95) fragment of the human CGbeta chain. Transgenic (TG) mice expressing the inhibin alpha-subunit promoter (inhalpha)/Simian Virus 40 T-antigen (Tag) transgene, developing luteinizing hormone (LH) receptor (R) expressing Leydig and granulosa cell tumors, and wild-type control littermates were treated either with vehicle, Hecate, or Hecate-CGbeta conjugate for 3 weeks. Hecate-CGbeta conjugate treatment reduced the testicular and ovarian tumor burden (P < .05), whereas a concomitant increase (testis; P < .05) or no change (ovary) in tumor volumes occured with Hectate treatment. A drop in serum progesterone, produced by the tumors, and an increase in LH levels occured in Hecate-CGbeta treated mice, in comparison with vehicle and Hecate groups, providing further support for the positive treatment response. Hecate-CGbeta conjugate induced a rapid and cell-specific membrane permeabilization of LHR-expressing cells in vitro, suggesting a necrotic mode of cell death without activation of apoptosis. These results prove the principle that the Hecate-CGbeta conjugate provides a novel specific lead into gonadal somatic cell cancer therapy by targeted destruction of LHR-expressing tumor cells.
Bodek
Gabriel
G
Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn 10-714, Poland.
Vierre
Susanna
S
Rivero-Müller
Adolfo
A
Huhtaniemi
Ilpo
I
Ziecik
Adam J
AJ
Rahman
Nafis A
NA
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002469:Cell Separation; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D005434:Flow Cytometry; D006106:Granulosa Cell Tumor / Q000628:therapy*; D006801:Humans; D007984:Leydig Cell Tumor / Q000628:therapy*; D008297:Male; D008555:Melitten / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009336:Necrosis; D010051:Ovarian Neoplasms / Q000628:therapy; D011374:Progesterone / Q000097:blood; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011974:Receptors, LH / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013736:Testicular Neoplasms / Q000628:therapy; D013997:Time Factors
D000590:Amino Acid Chloromethyl Ketones; D018997:Chorionic Gonadotropin, beta Subunit, Human; D011974:Receptors, LH; D011993:Recombinant Fusion Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C480619:hecate-chorionic gonadotropin beta-subunit conjugate; D008555:Melitten; D011374:Progesterone; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases