Protein phosphatase 2 phosphatase activator (PTPA) promotes oncogene-induced senescence and carboplatin response in human malignant pleural mesothelioma cells

Malignant pleural mesothelioma (MPM) is a rare cancer of the pleura, frequently related to asbestos exposure. It is characterized by a grim prognosis, as few therapeutic options are available. Typically, MPM exhibits high molecular heterogeneity, providing opportunities for exploiting therapeutic vulnerabilities in well-defined subgroups of patients. Nevertheless, these options have been insufficiently explored.

We found that inactivation of Protein Phosphatase 2A (PP2A) is a recurrent event in MPM, affecting the cancer cell phenotype and chemotherapy response. Specifically, in silico analysis showed that heterozygous loss of PTPA (PPP2R4), encoding the PP2A activator PTPA, occurred in 26% of MPM patients (TCGA, n = 87), correlating with significantly decreased overall survival. Re-expression of PTPA in PTPA-low human MPM cells decreased 2D colony formation and anchorage-independent cell growth, without affecting cell migration. At enzyme level, PTPA restoration increased PP2A catalytic subunit expression and activity (methylation), without favoring specific PP2A holoenzymes. Comparative RNAseq and Gene Set Enrichment Analysis revealed increased RAS pathway activation, activated p53 signaling and induction of senescence (SA-β-Galactosidase, SASP, NF-κB activation) upon PTPA restoration, presumably by increased PP2A-dependent dephosphorylation of Kinase Suppressor of Ras 1. Suppressing Ras signaling by Trametinib (MEK-inhibitor) prevented senescence induction, and pretreatment with senolytic agents restored impaired growth. ATUX-792, a pharmacologic PP2A activator, did not phenocopy senescence induction. Finally, PTPA restoration sensitized MPM cells to carboplatin as the likely consequence of lethal stress induction.

PTPA promotes oncogene-induced senescence (OIS) in MPM. By preventing OIS, heterozygous PTPA loss may contribute to mesothelial transformation and carboplatin resistance.