Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells

Abstract

Background:Activins control the growth of several tumour types including thoracic malignancies. In the present study, we investigated their expression and function in malignant pleural mesothelioma (MPM).Methods:The expression of activins and activin receptors was analysed by quantitative PCR in a panel of MPM cell lines. Activin A expression was further analysed by immunohistochemistry in MPM tissue specimens (N=53). Subsequently, MPM cells were treated with activin A, activin receptor inhibitors or activin-targeting siRNA and the impact on cell viability, proliferation, migration and signalling was assessed.Results:Concomitant expression of activin subunits and receptors was found in all cell lines, and activin A was overexpressed in most cell lines compared with non-malignant mesothelial cells. Similarly, immunohistochemistry demonstrated intense staining of tumour cells for activin A in a subset of patients. Treatment with activin A induced SMAD2 phosphorylation and stimulated clonogenic growth of mesothelioma cells. In contrast, treatment with kinase inhibitors of activin receptors (SB-431542, A-8301) inhibited MPM cell viability, clonogenicity and migration. Silencing of activin A expression by siRNA oligonucleotides further confirmed these results and led to reduced cyclin D1/3 expression.Conclusion:Our study suggests that activin A contributes to the malignant phenotype of MPM cells via regulation of cyclin D and may represent a valuable candidate for therapeutic interference.

Circulating activin A is a novel prognostic biomarker in malignant pleural mesothelioma – A multi-institutional study

“…Both our group and others have shown that activin A is expressed in MPM tissue and can play a protumourigenic role in MPM progression [3,4]. Here, we demonstrate that circulating activin A levels are also often elevated in MPM patients.…”

“…While in cancers of the breast, liver and colon, activin signals were found to inhibit tumour cell growth, and tumour tissue expressed decreased levels of activin A [11e14], in thoracic malignancies, including lung and oesophageal adenocarcinoma, increased activin A expression was associated with tumour cell aggressiveness [15e17]. Promotion of cell proliferation by activin A was demonstrated in oesophageal squamous cell carcinoma [17] and adenocarcinoma [16], lung adenocarcinoma [15] and also recently in MPM [3,4]. In lung and oesophageal adenocarcinoma, overexpression of activin A in tumour tissue is associated with poor prognosis, enhanced metastasis and/or a shorter disease-free survival time [15,17].…”

“…In previous studies, we and another group have shown that deregulated activin A signalling contributes to the malignant phenotype of MPM cells [3,4]. Activin A is a homodimer of two activin b A -chains that binds to transmembrane serine/threonine kinase receptor type II activin receptors.…”

An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

“…This finding demonstrates that, similar to the case of individual cytokines, blocking individual TGF-␤ family members such as myostatin alone may not be sufficient in settings such as cancer cachexia. Many human cancers present with altered expression of activin A, associated with a more malignant phenotype (22,23), and tumors can also induce the release of activin A from muscle (12). Intervention at the ActRIIB pathway level under cancer cachexia conditions in mice showed a clear benefit not only for muscle preservation but also for overall survival, without affecting tumor growth (24).…”

Activin A expression in esophageal carcinoma and its association with tumor aggressiveness and differentiation

“…Activin A plays an important role in cell proliferation, differentiation, apoptosis and adhesion (12)(13)(14). Recent studies have demonstrated that activin A expression is significantly increased in various types of cancer and is correlated with cancer progression and metastasis (15)(16)(17). However, to the best of our knowledge no studies have previously investigated the expression of activin A in esophageal cancer tissues.…”