Activin A Enhances Prostate Cancer Cell Migration Through Activation of Androgen Receptor and Is Overexpressed in Metastatic Prostate Cancer

Abstract

Bone metastasis is the major cause of mortality associated with prostate cancer. Whereas activin A is known to inhibit prostate cancer cell growth and promote apoptosis, the correlation of elevated activin A with increasing serum prostate-specific antigen (PSA) levels in bone metastatic stages of prostate cancer is well documented. The molecular mechanisms explaining these paradoxical effects of activin A and how activin A influences the progression of prostate cancer with bone metastasis remain unclear. By comparing expression profiles of primary prostate cancer biopsies, with and without bone metastasis, we discovered that the expression of activin A is increased in cases with bone metastatic propensity and correlates with increased androgen receptor (AR), PSA expression, and Gleason scores. Activin A promotes migration of prostate cancer cells to osteoblasts, elevates the AR gene transcription through Smads through binding to AR promoter, and induces nuclear translocation of AR to interact with Smad3. Knockdown of Smad3 by siRNA decreases activin A-promoted AR expression and cancer cell migration. Overexpression of AR reversed Smad3-siRNA suppression on activin A-mediated cell migration to osteoblasts. These data suggest that activation of the AR through Smads is required for activin A-promoted prostate cancer cell migration to bone matrix, thereby promoting the bone metastatic phenotype, and the activin A-Smad-AR axis may be considered a therapeutic target in bone metastatic diseases.

Activin A and bone metastasis

“…Furthermore, in prostate cancer patients Act A levels positively correlated with the number of bone lesions, increased prostate-specific antigen (PSA) serum concentrations and Gleason score. These findings are consistent with the recent immunohistochemical studies by Kang et al (2009), which reported that in human prostate cancer biopsies, Act A overexpression resulted significantly more frequent in metastatic patients than in nonmetastatic ones, and that also in this case, this phenomenon was closely associated with the Gleason score and PSA expression levels. In agreement with these findings, our studies, aiming to assess the clinical usefulness of circulating Act A as a gauge of metastatic bone diseases, showed a significant diagnostic effectiveness of this molecule in identifying patients with bone metastasis (Leto et al, 2006).…”

“…On the other hand, in the later phases of cancer progression, Act A appears to facilitate the dissemination of malignant cells towards target organs. Increasing evidence, in this regard, indicates that the prometastatic effects of this molecule appear to be correlated with activation multiple mechanisms, such as modulation of the expression of adhesion molecules (Jeruss et al, 2003;Yoshinaga et al, 2004;Tuck et al, 2007;Yoshinaga et al, 2008b;Kang et al, 2009;Simon et al, 2009;Murakami et al, 2010), interactions with motility factors and/or activation of hormone receptors through Smads (Hyuga et al, 2000;Jeruss et al, 2003;Kang et al, 2009) or upergulation of the expression levels of proteolytic enzymes involved in tumor cell invasion and metastasis (Ogawa et al, 2000;Mylonas et al, 2005;Leivonen et al, 2006;Wilson and Singh, 2008;Yoshinaga et al, 2008b;Kang et al, 2009;Simon et al, 2009). The potential contribute of Act A to foster, in particular, bone metastasis formation is supported by in vitro studies which show that this growth factor also appears to be implicated in the regulation of bone resorption during normal and pathological bone remodelling processes (Funaba et al, 1996;Sakai and Yuzuru, 2001;Gaddy-Kurten et al, 2002;Takeyama et al, 2005;Eiken et al, 2007;Nicks et al, 2009).…”

“…metastasize to the bone, such as breast cancer (Risbridger et al, 2001;Reis et al, 2004;Mylonas et al, 2005), lung cancer (Ogino et al, 2008;Seder et al, 2009), prostate cancer (Dowling and Risbridger, 2004;Fujii et al, 2004;Kang et al, 2009) and multiple myeloma (Vallet et al, 2008(Vallet et al, , 2010. Although the molecular pathways underlying the promoting effects of Act A on bone metastasis formation remain to be elucidated, growing evidence suggests that this molecule may facilitate this pathological process through different mechanisms (Table 2).…”

“…In particular, Smad2 knockdown results in the onset of a more aggressive phenotype (Petersen et al, 2010 Stimulation of osteoclast differentiation and activity Fuller et al (2000), Funaba et al (1996) Katoh, 2010), which facilitate bone metastasis formation. Interestingly, Kang et al (2009) et al, 2007). The interactions between bone marrow cells and tumor cells appears to be one of the key events through which tumor cells from multiple myeloma or prostate cancer may colonize bone tissue (Zhang et al, 2009;Vallet et al, 2010).…”

Activin A Is Anti-Lymphangiogenic in a Melanoma Mouse Model

“…However, activin A may also indirectly act proangiogenic through the induction of vascular endothelial growth factor (VEGF)-A expression in, e.g., hepatocellular carcinoma (Wagner et al, 2004) or in corneal epithelial cells (Poulaki et al, 2004). Activin A also has a two-edged role in cancer: in breast cancer and hepatoma cells, activin A inhibits cell growth and promotes apoptosis (Burdette et al, 2005), but it increases the migration of prostate cancer cells (Kang et al, 2009) and keratinocytes (Zhang et al, 2005). It is also associated with tumor progression and poor prognosis in oral squamous cell carcinoma (Chang et al, 2010).…”