Inhibition of bone morphogenetic protein receptor 2 suppresses pancreatic ductal adenocarcinoma growth by regulating GRB2/ PI3K/AKT axis

Abstract

Background: Bone morphogenetic protein receptor 2 (BMPR2) is an important transmembrane serine/ threonine kinase that involves oncogenic processes in multiple cancers. However, the role of BMPR2 and its regulatory mechanism in pancreatic ductal adenocarcinoma (PDAC) remain unknown. Methods: We performed a tissue array to explore the expression of BMPR2 in PDAC tissues. The Cell Counting Kit-8 (CCK-8) and colony formation assays were used to measure PDAC cells' proliferation. Proteomics and mass spectrometry technology was applied to analyze the BMPR2-regulating proteins. Flow cytometry was used to analyze the cell cycle distribution of PDAC cells. Orthotopic pancreatic cancer (PC) and patient-derived xenograft (PDX) models were used for in vivo experiments. Results: This study revealed the over-expression of BMPR2 in PDAC tissues and its proliferation-promoting role in PDAC cells. By carrying out protein mass spectrometry technique as well as bioinformatics analysis, we identified that BMPR2 regulated the growth factor receptor-bound protein 2/phosphatidylinositol 3-kinase/protein kinase B (GRB2/PI3K/AKT) signaling pathway, and further in vitro experiments showed that inhibition of BMPR2 resulted in suppressing proliferation and G2/M arrest by inhibiting the GRB2/PI3K/AKT signaling pathway in PDAC cells. The inhibition of BMPR2 by LDN193189 showed similar results in PDAC cells, orthotopic PC, and PDX models, which revealed that inhibition of BMPR2 significantly suppressed tumor growth by suppressing the GRB2/PI3K/AKT axis. Conclusions: Inhibition of BMPR2 suppresses PDAC growth by regulating the GRB2/PI3K/AKT axis and is a promising PDAC treatment strategy.