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Abstract
Abstract Activin A and B, members of the TGF-β superfamily, are regulators of differentiation, inflammation and wound healing. Dimeric activins bind to transmembrane activin type I and type II receptors and induce signaling through activation of the canonical Smad2/3 pathway as well as through activation of MAPK pathways. Depending on the tissue type activins can promote or inhibit cellular growth and/or migration. Activin A has recently been reported to have growth promoting properties in malignant mesothelioma (MM). MM is a rare and aggressive tumor originating most commonly from pleural mesothelial cells. It is asbestos exposure related malignancy that takes decades to develop. MM tumors are highly invasive and extremely resistant to conventional cancer therapy. Novel diagnostic markers and drug targets are urgently needed. We have characterized the expression of activins, follistatins and activin receptors in mesothelioma tumors and cultured mesothelioma cells. In addition, we have identified signaling pathways induced in mesothelioma cells by activin treatment. Expression of activins and receptors in mesothelioma tumors were analyzed by immunohistochemistry. Activins, follistatins and receptors in primary mesothelioma cells and in mesothelioma cell lines were analyzed at the level of mRNA and protein expression. Activation of Smad2/3 and Smad1/5/8 signaling pathways were analyzed by luciferase reporter assays and Western blotting. Activation of MAPK/JNK and MAPK/ERK pathways were analyzed by Western blotting. Immortalized but nonmalignant Met5A cells served as a control cell line. Activin A and B were strongly expressed in mesothelioma tumor tissue. Cultured primary mesothelioma cells and mesothelioma cell lines also expressed higher levels of activin A and B compared to Met5A cells. All activin receptors (ALK3, ALK4, ALK7, ACVR2A, ACVR2B) were found expressed in cultured mesothelioma cells. ACVR2A and ALK7 were significantly overexpressed in all mesothelioma cells. Majority of the mesothelioma cell lines had attenuated Smad2/3 activation upon activin stimulation. In Met5A and H28 cells there was activation of Smad2/3 as well as MAPK/JNK pathways. On the contrary, activation of MAPK/ERK pathway was detected in cells displaying attenuated Smad2/3 activation.Our results show that activin A and B are overexpressed in MM. This together with upregulation of specific activin receptors points to a role for activins in MM progression. Furthermore, we observed that mesothelioma cells have altered responses to activin stimulation, namely attenuation of canonical Smad2/3 signaling and increase in MAPK/ERK signaling. This is likely to have an impact on mesothelioma cell behavior and tumor progression. Citation Format: Jenni A. Tamminen, Mikko Rönty, Eva Sutinen, Arja Pasternack, Olli Ritvos, Marjukka Myllärniemi, Katri Koli. Overexpression of activin A and B as well as altered activation of canonical and non-canonical signaling pathways in malignant mesothelioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3449. doi:10.1158/1538-7445.AM2014-3449
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