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Truncating mutations in the ACVR2 gene attenuates activin signaling in prostate cancer cells
Michael R Rossi1, Yurij Ionov, Andrei V Bakin
1Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Abstract:
Activins are classified as members of the TGFbeta superfamily of signaling molecules and both activin and TGFbeta ligands signal through structurally and functionally related serine/threonine kinase receptors. Defects in these signaling pathways have been associated with the initiation and progression of the cancer phenotype. Inactivating mutations in the TGFbeta type II receptor gene, TGFbetaR2, have been identified in a variety of tumors and cell lines, particularly those with microsatellite instability (MSI). More recently, mutations in the activin type II receptor gene, ACVR2, were identified in colon and pancreatic cell lines and tumors with MSI. Because prostate tumors appear to have a high incidence of MSI, we analyzed prostate cancer cell lines, with and without MSI, for ACVR2 and TGFbetaR2 mutations. Our analysis of 6 prostate cell lines revealed mutations in the ACVR2 gene in 22Rv-1, LAPC-4, DU145, and LNCaP cells and mutations in the TGFbetaR2 gene in 22Rv-1 and LAPC-4. PC3 and H660 cells were wild-type for ACVR2 and TFGbetaR2. All of the ACVR2 mutations were truncating mutations, and using an activin response assay, we demonstrate that truncating mutations of the ACVR2 gene result in a significant reduction in activin mediated cell signaling. Inactivation of ACVR2 is a common event in prostate cancer cells suggesting it may play an important role in the development of prostate cancer.
Insights
Mutations in the activin type II receptor gene (ACVR2) are common in prostate cancer cells, potentially contributing to cancer development. These ACVR2 gene defects reduce activin signaling, impacting cell growth.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Activins and TGFbeta ligands are crucial signaling molecules within the TGFbeta superfamily.
- Defects in these signaling pathways are implicated in cancer initiation and progression.
- Mutations in TGFbeta type II receptor (TGFbetaR2) and activin type II receptor (ACVR2) genes are found in various cancers, particularly those with microsatellite instability (MSI).
Purpose of the Study:
- To investigate mutations in ACVR2 and TGFbetaR2 genes in prostate cancer cell lines.
- To determine the functional impact of ACVR2 mutations on activin signaling.
- To assess the role of ACVR2 inactivation in prostate cancer development.
Main Methods:
- Analysis of ACVR2 and TGFbetaR2 gene sequences in six prostate cancer cell lines.
- Identification of mutations using standard molecular biology techniques.
- Assessment of ACVR2 function through an activin response assay.
Main Results:
- Mutations in ACVR2 were identified in 22Rv-1, LAPC-4, DU145, and LNCaP prostate cancer cell lines.
- Mutations in TGFbetaR2 were found in 22Rv-1 and LAPC-4 cell lines.
- All identified ACVR2 mutations were truncating, leading to significantly reduced activin-mediated cell signaling.
Conclusions:
- Inactivation of the ACVR2 gene is a frequent event in prostate cancer cells.
- ACVR2 mutations may play a significant role in the development of prostate cancer.
- Further research into ACVR2's role in prostate cancer pathogenesis is warranted.
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