BMP9-Induced Survival Effect in Liver Tumor Cells Requires p38MAPK Activation.
The study of bone morphogenetic proteins (BMPs) role in tumorigenic processes, and specifically in the liver, has gathered importance in the last few years. Previous studies have shown that BMP9 is overexpressed in about 40% of hepatocellular carcinoma (HCC) patients. In vitro data have also shown evidence that BMP9 has a pro-tumorigenic action, not only by inducing epithelial to mesenchymal transition (EMT) and migration, but also by promoting proliferation and survival in liver cancer cells. However, the precise mechanisms driving these effects have not yet been established. In the present work, we deepened our studies into the intracellular mechanisms implicated in the BMP9 proliferative and pro-survival effect on liver tumor cells. In HepG2 cells, BMP9 induces both Smad and non-Smad signaling cascades, specifically PI3K/AKT and p38MAPK. However, only the p38MAPK pathway contributes to the BMP9 growth-promoting effect on these cells. Using genetic and pharmacological approaches, we demonstrate that p38MAPK activation, although dispensable for the BMP9 proliferative activity, is required for the BMP9 protective effect on serum withdrawal-induced apoptosis. These findings contribute to a better understanding of the signaling pathways involved in the BMP9 pro-tumorigenic role in liver tumor cells.
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid. San Carlos Clinical Hospital Health Research Institute (IdISSC), Plaza Ramón y Cajal S/N, Madrid 28040, Spain. mariagarciaalvaro@gmail.com.
María
M
García-Álvaro
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid. San Carlos Clinical Hospital Health Research Institute (IdISSC), Plaza Ramón y Cajal S/N, Madrid 28040, Spain. aaddante@ucm.es.
Annalisa
A
Addante
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid. San Carlos Clinical Hospital Health Research Institute (IdISSC), Plaza Ramón y Cajal S/N, Madrid 28040, Spain. ceronce@ucm.es.
Cesáreo
C
Roncero
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid. San Carlos Clinical Hospital Health Research Institute (IdISSC), Plaza Ramón y Cajal S/N, Madrid 28040, Spain. margafdz@ucm.es.
Margarita
M
Fernández
Bellvitge Biomedical Research Institute (IDIBELL) and University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona 08908, Spain. ifabregat@idibell.cat.
Isabel
I
Fabregat
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid. San Carlos Clinical Hospital Health Research Institute (IdISSC), Plaza Ramón y Cajal S/N, Madrid 28040, Spain. munozas@ucm.es.
Aránzazu
A
Sánchez
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid. San Carlos Clinical Hospital Health Research Institute (IdISSC), Plaza Ramón y Cajal S/N, Madrid 28040, Spain. blancamh@ucm.es.
Blanca
B
Herrera
D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000378:metabolism* / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D002867:Chromones; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases; C525887:GDF2 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
BMP9; PI3K; apoptosis; liver cancer; non-Smad; p38MAPK