Inhibition of protein phosphatase 5 suppresses non-small cell lung cancer through AMP-activated kinase activation

[Display omitted] •PP5 is highly expressed in human lung tumor samples.•Overexpression of PP5 promotes NSCLC cell growth and sphere formation.•PP5 inhibition shows anti-NSCLC activity via upregulating AMPK signaling.•Targeting PP5 pathway is a potential therapy for NSCLC. Non-small cell lung cancer (NSCLC) continues to be the top cause of cancer death. To improve the treatment of lung cancer, there is necessity to identify novel oncogenes and investigate their effects on lung carcinogenesis. Protein phosphatase 5 (PP5) has long been known to regulate stress-induced apoptosis and cell proliferation. Recently, PP5 has been found overexpressed and emerged as a viable therapeutic target in various human cancers, but its role in NSCLC remains elusive. The expression of PP5 in NSCLC cell lines (A549, H358, and H460) and human tumor samples were examined. Protein phosphatase inhibitors, cantharidin and norcantharidin, were used as proof-of-concept compounds to investigate the pathological function of PP5 in NSCLC. Apoptosis and cellular signaling were analyzed. In vivo efficacy was determined in nude mice with H460 xenograft. We found that PP5 was more highly expressed in human lung tumor samples than in adjacent normal tissues. Overexpression of PP5 promoted cell proliferation, colony formation, and sphere-forming ability of A549 cells. Inhibition of PP5 phosphatase activity by cantharidin induced significant apoptosis and upregulated AMP‐activated protein kinase (AMPK) signaling. Importantly, we found that PP5-mediated dephosphorylation of AMPK determines the in vitro anti‐NSCLC effects of cantharidin. Consistent with our in vitro data, PP5 inhibition suppressed H460 tumor growth and upregulated p‐AMPK in tumor samples. Our results demonstrate that PP5 inhibition suppresses tumor growth via activating AMPK signaling. Targeting oncogenic PP5 represents an attractive therapeutic strategy for treating lung cancer.