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Hecate-FSHβ33-53C/S lytic peptide conjugate selectively kills targeted follicle stimulating hormone receptor
Nafis A Rahman1, Marcin Chrusciel2, Donata Ponikwicka-Tyszko3
1Institute of Biomedicine, University of Turku, Finland; Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Poland.
Background:
The follicle stimulating hormone (FSH) receptor (FSHR), is expressed primarily in the gonads, also found in ovarian and prostate cancers, and in tumor vessel endothelial cells. We investigated the potential of a targeted cytotoxic approach using Hecate-FSHβ, a conjugate derived from a lytic peptide Hecate, an analog of bee venom melittin, and the β subunit of FSH, to selectively eliminate FSHR-positive cancer cells.
Methods:
Hecate-FSHβ-mediated cytotoxicity was tested in human granulosa tumor cell line KGN, human embryonic kidney HEK-293 cell line stably transfected with human FSHR cDNA (HEK293-FSHR) and mock-transfected HEK-293 cells as FSHR-negative control cells. Tested variant Hecate-FSHβ33-53C/S with cysteine residues replaced by serine, was evaluated for its cytotoxicity towards FSHR-positive cells.
Results:
Hecate-FSHβ33-53C/S demonstrated the highest specific cytotoxicity towards FSHR-positive cells (KGN and HEK293-FSHR vs. control). In competition studies, cotreatment with recombinant human FSH (rhFSH) reduced the cytotoxic effect of the conjugate on these cells, highlighting FSHR specificity. In xenograft models of HEK293-FSHR, Hecate-FSHβ33-53C/S alone or in combination with a gonadotropin releasing hormone (GnRH) antagonist (Cetrorelix, CTX) significantly inhibited tumor growth. No synergistic effect was observed with co-administered Hecate-FSHβ33-53C/S and CTX. Hecate-FSHβ33-53C/S induced necrosis in tumor cells, whereas CTX triggered apoptosis. Hecate-FSHβ33-53C/S did not produce any side effects. CTX treatment caused increased spleen size and inhibited spermatogenesis, leading to reduced testis weight, which aligns with expected gonadal effects.
Conclusions:
Hecate-FSHβ33-53C/S is highly effective in selectively targeting and killing FSHR-expressing cancer cells, with minimal side effects, suggesting its potential as a therapeutic option for cancers expressing FSH receptors.
Insights
A novel conjugate, Hecate-FSHβ33-53C/S, selectively targets and eliminates follicle stimulating hormone receptor (FSHR)-positive cancer cells. This targeted therapy shows significant tumor inhibition with minimal side effects, offering a promising new treatment option.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Follicle stimulating hormone receptor (FSHR) is expressed in gonads, ovarian cancer, prostate cancer, and tumor vasculature.
- Investigating targeted cytotoxic therapies for FSHR-positive cancers is crucial.
Purpose of the Study:
- To evaluate the efficacy and specificity of Hecate-FSHβ, a conjugate of a lytic peptide and FSH β-subunit, for eliminating FSHR-positive cancer cells.
- To assess a specific variant, Hecate-FSHβ33-53C/S, for its targeted cytotoxicity.
Main Methods:
- Cytotoxicity assays were performed using FSHR-positive (KGN, HEK293-FSHR) and FSHR-negative (HEK293) cell lines.
- Competition studies with recombinant human FSH (rhFSH) assessed conjugate specificity.
- In vivo efficacy was evaluated in HEK293-FSHR xenograft models, with and without a GnRH antagonist (Cetrorelix).
Main Results:
- Hecate-FSHβ33-53C/S demonstrated high, specific cytotoxicity against FSHR-positive cancer cells.
- rhFSH competition confirmed the conjugate's FSHR specificity.
- In vivo, Hecate-FSHβ33-53C/S significantly inhibited tumor growth in xenografts, with no observed side effects.
- Combination therapy with a GnRH antagonist did not yield synergistic effects; distinct mechanisms of cell death were observed (necrosis vs. apoptosis).
Conclusions:
- Hecate-FSHβ33-53C/S effectively targets and eliminates FSHR-expressing cancer cells.
- The conjugate exhibits a favorable safety profile with minimal side effects.
- This targeted approach holds significant therapeutic potential for FSHR-positive malignancies.
