Secreted Stress-Induced Phosphoprotein 1 Activates the ALK2-SMAD Signaling Pathways and Promotes Cell Proliferation of Ovarian Cancer Cells

• Published in: Cell reports (Cambridge) 2012-08, Vol.2 (2), p.283-293
• Main Authors: Tsai, Chia-Lung, Tsai, Chi-Neu, Lin, Chiao-Yun, Chen, Hsi-Wen, Lee, Yun-Shien, Chao, Angel, Wang, Tzu-Hao, Wang, Hsin-Shih, Lai, Chyong-Huey
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type I - genetics; Activin Receptors, Type I - metabolism; Cell Line, Tumor; Cell Proliferation; Female; Heat-Shock Proteins - genetics; Heat-Shock Proteins - secretion; Humans; Inhibitor of Differentiation Proteins - genetics; Inhibitor of Differentiation Proteins - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovarian Neoplasms - therapy; Protein Binding; Signal Transduction; Smad Proteins - genetics; Smad Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.07.002

Stress-induced phosphoprotein 1 (STIP1), a cochaperone that organizes other chaperones, heat shock proteins (HSPs), was recently shown to be secreted by human ovarian cancer cells. In neuronal tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular-regulated MAP kinase) signaling pathways. However, we report that STIP1 binding to a bone morphogenetic protein (BMP) receptor, ALK2 (activin A receptor, type II-like kinase 2), was necessary and sufficient to stimulate proliferation of ovarian cancer cells. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3), promoting cell proliferation. In conclusion, ovarian-cancer-tissue-secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Although animal studies are needed to confirm these mechanisms in vivo, our results may pave the way for developing novel therapeutic strategies for ovarian cancer. [Display omitted] ► Ovarian cancer tissues secrete STIP1 into blood circulation ► rhSTIP1 may bind to BMP receptor ALK2 and activate the SMAD1/SMAD5-ID3 pathway ► The STIP1-ALK2 pathway stimulates cell proliferation in ovarian cancer cells STIP1 is a cochaperone for heat shock proteins. When secreted by neuronal cells, STIP1 was shown to bind to prion membrane protein and activate ERK pathways. Herein, Chao, Wang, and colleagues report that the ovarian-cancer-tissue-secreted STIP1 binds to a BMP receptor, ALK2, to activate SMAD1/SMAD5 pathways and upregulate ID3 expression, leading to cancer cell proliferation. These results not only provide insights into the tumorigenesis of ovarian cancer but also pave the way for developing novel therapeutic strategies.