Activin A inhibits vascular endothelial cell growth and suppresses tumour angiogenesis in gastric cancer

Autor: Kazuko Sakai, Kazuyoshi Yanagihara, Tokuzo Arao, Keita Kudo, M. A. De Velasco, Yoshihiko Fujita, Kazuto Nishio, Yuki Yamada, Kazuhiko Nakagawa, Hiroyasu Kaneda, Isamu Okamoto, Kazuko Matsumoto, Keiichi Aomatsu, Tomoyuki Nagai, Daisuke Tamura, Kaoru Tanaka
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Zdroj: British Journal of Cancer
ISSN: 1532-1827
0007-0920
Popis: Activins are homodimers formed by the assembly of two closely related inhibin β subunits, βA and βB, which generate three isoforms, activin A (βA–βA), activin B (βB–βB), and activin AB (βA–βB) (Chen et al, 2002). Activin A is a member of the transforming growth factor (TGF-β) superfamily and shares the Smad intracellular signalling proteins with TGF-β (Shi and Massague, 2003). Activin A binds to activin type II receptors, ActR-II and ActR-IIB, and the ligand/type II receptor complex then recruits, binds, and phosphorylates the type I receptor ActR-IB, also known as activin receptor-like kinase 4 (ALK4), resulting in the propagation of the signal downstream. The activation of ALK4 kinase phosphorylates and activates the cytoplasmic signalling molecules Smad2 or Smad3, and a specific activated Smad complex then translocates and accumulates in the nucleus, where it is involved in the transcriptional regulation of target genes (Shi and Massague, 2003). Activins have been found to control a wide spectrum of biological effects, such as cellular growth and developmental differentiation in many cell types, although it was originally described as a regulator of follicle-stimulating hormone release from the anterior pituitary (Ying, 1988; Dawid et al, 1992; Munz et al, 2001; Shav-Tal and Zipori, 2002). Recently, activin A has been reported as an essential growth factor involved in embryonic stem cell renewal and pluripotency (Xiao et al, 2006; Jiang et al, 2007). In general, activin A causes growth inhibition in epithelial cells ranging from many normal mesenchymal and haematopoietic cells to a variety of cancer cells. In addition, activin A not only inhibits cell proliferation, but it also induces apoptosis in multiple cells and tissues. For example, activin A inhibits the cellular proliferation of breast cancer T47D cells by enhancing the expression of p15 cyclin-dependent kinase (cdk) inhibitors, and the overexpression of activin A in human prostate cancer LNCaP cells inhibited proliferation, induced apoptosis, and decreased the tumourigenicity of these cells (Zhang et al, 1997; Burdette et al, 2005). In addition, activin A also reportedly exerts a tumour suppressor function in human neuroblastoma cells (Panopoulou et al, 2005). In angiogenetic roles, emerging evidence has demonstrated that TGF-β, the other superfamily member, may definitely stimulate angiogenesis during the late stage of cancer (Jakowlew, 2006), while neuroblastoma cells with restored activin A expression exhibit a decreased tumour growth and reduced vascularity (Panopoulou et al, 2005). Collectively, whether activin A inhibits angiogenesis in other cancers in addition to its underlying mechanism resulting in the growth inhibition of vascular endothelial cells remains unclear. We previously performed a microarray analysis of paired gastric cancer (GC) and non-cancerous gastric mucosa samples and identified the overexpression of INHBA in the GC samples (Yamada et al, 2008 and unpublished data). Based on this finding of INHBA overexpression and accumulating evidence of the role of TGF-β in angiogenesis, we focused on the role of activin A in angiogenesis in GC in the present study.
Databáze: OpenAIRE
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