PP2A inhibitor PME-1 suppresses anoikis, and is associated with therapy relapse of PTEN-deficient prostate cancers
AbstractIdentification of novel mechanisms of apoptosis resistance of prostate cancer (PCa) cells has translational importance. Here, we discover that inhibition of tumor suppressor phosphatase PP2A by PME-1 inhibits anoikis (apoptosis in anchorage-independent conditions) in PTEN-deficient PCa cells. PME-1 physically associated with the nuclear lamina and regulated its deformability in PCa cells. In addition, PME-1 deficient cells, with highly deformable nuclear lamina, were particularly vulnerable to anoikis following cell detachment. As a molecular explanation for increased nuclear lamina deformability, PME-1 depletion induced dephosphorylation of nuclear lamina constituents, Lamin-A/C, Lamin-B1, Lamin-B2, LAP2A, LAP2B, and NUP98. PME-1 inhibition increased apoptosis also in anin ovotumor model, and attenuated cell survival in zebrafish circulation. Clinically, PCa patients with inhibition of both PP2A and PTEN tumor suppressor phosphatases (PME-1high/PTENloss), have less than 50% 5-year secondary-therapy free patient survival, which is significantly shorter than survival of patients with only PTEN-deficient tumors.In summary, we discover that PME-1 overexpression supports anoikis resistance in PTEN-deficient PCa cells. Further, increased nuclear lamina deformability was identified as plausible target mechanism sensitizing PME-1-depleted cells to anoikis. Clinically, the results identify PME-1 as a novel candidate biomarker for particularly aggressive PTEN-deficient PCa.Clinical relevanceWhile organ-confined PCa is mostly manageable, the local and distant metastatic progression of PCa remains a clinical challenge. Resistance to anoikis is critical for PCa progression towards aggressive CRPC. Our data show that PME-1 expression in human PCa cells protects the cells from apoptosis induction in anchorage-independent conditions bothin vitroandin vivo. Clinically, our results identify PME-1 as a novel putative biomarker for extremely poor prognosis in PTEN-deficient PCa. Taken together, our results demonstrate novel post-translational regulation of key cancer progression mechanisms, with clear translational implications.
