Nodal and ALK7 Inhibit Proliferation and Induce Apoptosis in Human Trophoblast Cells

Abstract

Nodal, a member of the transforming growth factor-␤ superfamily, is known to play critical roles in early vertebrate development, but its functions in extraembryonic tissues are unclear. ALK7 is a type I receptor for Nodal. Recently, we demonstrated that Nodal mRNA and several ALK7 transcripts are expressed in human placenta throughout pregnancy (Roberts, H. J., Hu, S., Qiu, Q., Leung, P. C. K., Cannigia, I., Gruslin, A., Tsang, B., and Peng, C. (2003) Biol. Reprod. 68, 1719 -1726). In this study, we determined the role of Nodal and ALK7 in trophoblast cell proliferation and apoptosis. Overexpression of Nodal in normal trophoblast cells (HTR8/ SVneo) and several choriocarcinoma cell lines resulted in a significant decrease in the number of metabolically active cells. The effect of Nodal could be mimicked by constitutively active ALK7 (ALK7-ca), but was blocked by kinase-deficient ALK7. The growth inhibitory effect of Nodal was also blocked by dominant-negative Smad2/3. Overexpression of Nodal and ALK7-ca induced apoptosis in trophoblast cells as determined by Hoechst staining, flow cytometry, and caspase-3 Western blotting. In addition, Nodal and ALK7-ca decreased the number of proliferating cells as measured by bromodeoxyuridine assays. Furthermore, overexpression of Nodal or ALK7-ca increased p27 expression, but reduced the levels of Cdk2 and cyclin D 1 . Taken together, this study demonstrates for the first time that Nodal, acting through ALK7 and Smad2/3, inhibits proliferation and induces apoptosis in human trophoblast cells. Our findings also suggest that the Nodal-ALK7 pathway inhibits cell proliferation by inducing G 1 cell cycle arrest and that this effect is mediated in part by the p27-cyclin E/Cdk2 pathway.

Overexpression of Activin Receptor-like Kinase 7 in Breast Cancer Cells Is Associated with Decreased Cell Growth and Adhesion

“…ALK7 influences cell proliferation and induces cell apoptosis and these effects have been found in a rat neuronal cell line, hepatoma cells, human trophoblast cells and ovarian cancer cells (12,(14)(15)(16)19). We also found a similar phenomenon in breast cancer cell lines MDA-MB-231 and MCF-7 and this was consistent with the result from a study on ZR-75-30 breast cancer cell (17).…”

“…In addition, constitutively activated ALK7 induces apoptosis of hepatoma and pancreatic β cells (12,13). Nodal acts via ALK7 to inhibit proliferation and induce apoptosis of human trophoblast cells (14), and epithelial ovarian cancer cells (15,16). These findings support the role of nodal-ALK7 pathway in mediating cell proliferation and apoptosis of cancer cells.…”

“…Activation of ALK7 was shown to inhibit cell proliferation and to induce morphological differentiation in the rat neuronal cell line PC12 (11) ALK7 also induced apoptosis in a variety of cell types, such as hepatoma, trophoblast, epithelial ovarian cancer cells (12,15,16). Nodal has similar growth-inhibiting, apoptosis-inducing effects to ALK7 on trophoblast and ovarian cancer cells (14). Previous studies have shown that nodal, acting through ALK7 and SMAD2/3, exerts antiproliferative and apoptotic effects on human trophoblast and ovarian cancer cells (15,16,32).…”

Nodal signalling and asymmetry of the nervous system

“…It is known, for example, that Nodal signalling can maintain pluripotency and prevent differentiation to neuroectoderm in human embryonic stem cells (hESC) and mouse epiblastderived stems cells (mEpiSC) [32] while it is necessary for endoderm differentiation in pluripotent cells and the mouse gastrula embryo [3,33]. Similarly, Nodal can inhibit cell migration, invasion and proliferation in human trophoblasts [34,35] while it promotes the opposite in human glioma and breast cancer cells [36,37]. Such divergent mechanisms create the necessity of developing a conceptual framework to help recognize L-R patterns and assess the phenomenon in a meaningful manner.…”

ALK7 Gene Polymorphism is Associated with Metabolic Syndrome Risk and Cardiovascular Remodeling

“…Our results showed that both blood pressure and LVMI were associated with rs13010956, suggesting a potential role of the ALK7 gene polymorphism in the early stages of diastolic heart failure. Previous studies have revealed the significance of ALK7 in cell apoptosis and proliferation 13,27,28 . However, whether the ALK7 gene polymorphism contributes to cardiac remodeling and heart dysfunction by playing a role in myocardial apoptosis and fibrosis needs to be determined in the future.…”