Abstract
Identification 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 an in ovo tumor 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 relevance While 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 both in vitro and in 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.