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Activin B and Activin C Have Opposing Effects on Prostate Cancer Progression and Cell Growth.

ABSTRACT: Current prognostic and diagnostic tests for prostate cancer are not able to accurately distinguish between aggressive and latent cancer. Members of the transforming growth factor-β (TGFB) family are known to be important in regulating prostate cell growth and some have been shown to be dysregulated in prostate cancer. Therefore, the aims of this study were to examine expression of TGFB family members in primary prostate tumour tissue and the phenotypic effect of activins on prostate cell growth. Tissue cores of prostate adenocarcinoma and normal prostate were immuno-stained and protein expression was compared between samples with different Gleason grades. The effect of exogenous treatment with, or overexpression of, activins on prostate cell line growth and migration was examined. Activin B expression was increased in cores containing higher Gleason patterns and overexpression of activin B inhibited growth of PNT1A cells but increased growth and migration of the metastatic PC3 cells compared to empty vector controls. In contrast, activin C expression decreased in higher Gleason grades and overexpression increased growth of PNT1A cells and decreased growth of PC3 cells. In conclusion, increased activin B and decreased activin C expression is associated with increasing prostate tumor grade and therefore have potential as prognostic markers of aggressive prostate cancer.

SUBMITTER: Reader KL

PROVIDER: S-EPMC9817897 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Activin B and Activin C Have Opposing Effects on Prostate Cancer Progression and Cell Growth.

Reader Karen L KL John-McHaffie Simon S Zellhuber-McMillan Sylvia S Jowett Tim T Mottershead David G DG Cunliffe Heather E HE Gold Elspeth J EJ

Cancers 20221227 1

Current prognostic and diagnostic tests for prostate cancer are not able to accurately distinguish between aggressive and latent cancer. Members of the transforming growth factor-β (TGFB) family are known to be important in regulating prostate cell growth and some have been shown to be dysregulated in prostate cancer. Therefore, the aims of this study were to examine expression of TGFB family members in primary prostate tumour tissue and the phenotypic effect of activins on prostate cell growth. ...[more]

PMID: 36612143

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Project description:Anti‑Müllerian hormone (AMH) type II receptor (AMHRII) and the AMH/AMHRII signaling pathway are potential therapeutic targets in ovarian carcinoma. Conversely, the role of the three AMH type I receptors (AMHRIs), namely activin receptor‑like kinase (ALK)2, ALK3 and ALK6, in ovarian cancer remains to be clarified. To determine the respective roles of these three AMHRIs, the present study used four ovarian cancer cell lines (COV434‑AMHRII, SKOV3‑AMHRII, OVCAR8, KGN) and primary cells isolated from tumor ascites from patients with ovarian cancer. The results demonstrated that ALK2 and ALK3 may be the two main AMHRIs involved in AMH signaling at physiological endogenous and supraphysiological exogenous AMH concentrations, respectively. Supraphysiological AMH concentrations (25 nM recombinant AMH) were associated with apoptosis in all four cell lines and decreased clonogenic survival in COV434‑AMHRII and SKOV3‑AMHRII cells. These biological effects were induced via ALK3 recruitment by AMHRII, as ALK3‑AMHRII dimerization was favored at increasing AMH concentrations. By contrast, ALK2 was associated with AMHRII at physiological endogenous concentrations of AMH (10 pM). Based on these results, tetravalent IgG1‑like bispecific antibodies (BsAbs) against AMHRII and ALK2, and against AMHRII and ALK3 were designed and evaluated. In vivo, COV434‑AMHRII tumor cell xenograft growth was significantly reduced in all BsAb‑treated groups compared with that in the vehicle group (P=0.018 for BsAb 12G4‑3D7; P=0.001 for all other BsAbs). However, the growth of COV434‑AMHRII tumor cell xenografts was slower in mice treated with the anti‑AMRII‑ALK2 BsAb 12G4‑2F9 compared with that in animals that received a control BsAb that targeted AMHRII and CD5 (P=0.048). These results provide new insights into type I receptor specificity in AMH signaling pathways and may lead to an innovative therapeutic approach to modulate AMH signaling using anti‑AMHRII/anti‑AMHRI BsAbs.

Dataset Information

Activin B and Activin C Have Opposing Effects on Prostate Cancer Progression and Cell Growth.

Publications

Activin B and Activin C Have Opposing Effects on Prostate Cancer Progression and Cell Growth.

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