Altered PPP2R4 (PTPA) expression affects growth and carboplatin response of human malignant pleural mesothelioma cells

ABSTRACT: Malignant pleural mesothelioma (MPM) is a rare cancer of the pleural surfaces, frequently related to asbestos exposure. It is characterized by a grim prognosis and low survival, as few therapeutic options are currently available. Molecular genomics studies have revealed high molecular heterogeneity, which may provide possibilities for exploiting therapeutic vulnerabilities in well-defined subgroups of patients. However, the latter avenues have been insufficiently explored to date. Here, we found that inactivation of Protein Phosphatase 2A (PP2A) is a recurrent event in MPM, affecting both the cancer cell phenotype as well as its response to chemotherapy. Specifically, heterozygous loss of PPP2R4, encoding the PP2A Activator PTPA, occurred in 26% of MPM patients (TCGA, n=87), correlating with a significant decrease in overall survival. Re-expression of PTPA in PTPA-low human MPM cells decreased 2D colony growth as well as anchorage-independent growth, without affecting 2D cell migration. Biochemically, PTPA re-expression increased PP2A catalytic C subunit expression and activity (methylation), without favoring any specific PP2A holoenzymes. Comparative RNAseq and Gene Set Enrichment Analysis revealed increased RAS pathway activation, activated p53 signaling and induction of senescence (SASP and NF-κB activation) upon PTPA restoration, presumably by increased PP2A-dependent dephosphorylation of KSR1. Moreover, PTPA restoration increased MPM cell sensitivity to carboplatin, correlating with a incresead DNA Damage Response (DDR; decreased ATR phosphorylation) and increased DNA-damage (γH2AX).

ORGANISM(S): Homo sapiens

PROVIDER: GSE312009 | GEO | 2026/08/19

REPOSITORIES: GEO