PDGF regulates proliferation of malignant mesothelioma cells via CTGF protein control

Abstract

Abstract Malignant mesothelioma (MM) is a disease caused by exposure to refractory asbestos. The number of patients constantly increases globally because of the 20-40-year latency period. This study aimed to perform small-molecule inhibitor screening to explore MM cell signaling and identify new targets for molecular therapy. Our results show that not only platelet-derived growth factor receptor (PDGFR) inhibitors but also small interfering RNA that target PDGFR-α or PDGFR-β suppressed the proliferation of MM cell lines. Knockdown of PDGFR-α and PDGFR-β expression reduced connective tissue growth factor (CTGF) protein expression, which is known to affect MM cell proliferation and malignancy. Platelet-derived growth factor (PDGF) treatment induced the elevation of CTGF protein within 30 min without affecting CTGF mRNA levels in MM cells. Based on the knowledge that the protein kinase B (AKT)-mTOR pathway participates in mRNA translational control, we found that PDGF activates AKT/mTOR signaling in MM cells, and the blockade of AKT activation inhibited CTGF protein upregulation induced by PDGF. These results demonstrated that the proliferation of MM cells was significantly controlled by the PDGF–AKT–CTGF pathway. Our findings suggest that PDGF–PDGFR may be a possible therapeutic target in patients with MM.