PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers

Abstract

33Identification of novel mechanisms of apoptosis resistance of prostate cancer (PCa) 34 cells has translational importance. Here, we discover that inhibition of tumor 35 suppressor phosphatase PP2A by PME-1 inhibits anoikis (apoptosis in anchorage-36 independent conditions) in PTEN-deficient PCa cells. PME-1 physically associated 37 with the nuclear lamina and regulated its deformability in PCa cells. In addition, PME-38 1 deficient cells, with highly deformable nuclear lamina, were particularly vulnerable to 39 anoikis following cell detachment. As a molecular explanation for increased nuclear 40 lamina deformability, PME-1 depletion induced dephosphorylation of nuclear lamina 41 constituents, Lamin-A/C, Lamin-B1, Lamin-B2, LAP2A, LAP2B, and NUP98. PME-1 42 inhibition increased apoptosis also in an in ovo tumor model, and attenuated cell 43 survival in zebrafish circulation. Clinically, PCa patients with inhibition of both PP2A 44 and PTEN tumor suppressor phosphatases (PME-1 high /PTEN loss ), have less than 50% 455-year secondary-therapy free patient survival, which is significantly shorter than 46 survival of patients with only PTEN-deficient tumors. 47In summary, we discover that PME-1 overexpression supports anoikis 48 resistance in PTEN-deficient PCa cells. Further, increased nuclear lamina 49 deformability was identified as plausible target mechanism sensitizing PME-1-50 depleted cells to anoikis. Clinically, the results identify PME-1 as a novel candidate 51 biomarker for particularly aggressive PTEN-deficient PCa. 52 53 55 56 3 57 Clinical relevance 58 59 While organ-confined PCa is mostly manageable, the local and distant metastatic 60 progression of PCa remains a clinical challenge. Resistance to anoikis is critical for 61 PCa progression towards aggressive CRPC. Our data show that PME-1 expression in 62 human PCa cells protects the cells from apoptosis induction in anchorage-63 independent conditions both in vitro and in vivo. Clinically, our results identify PME-1 64 as a novel putative biomarker for extremely poor prognosis in PTEN-deficient PCa. 65 Taken together, our results demonstrate novel post-translational regulation of key 66 cancer progression mechanisms, with clear translational implications. 67 68 (4), and prostate-specific PTEN deletion in a mouse model leads to metastatic PCa 87 (5). Importantly, both PTEN deletion, and hyperactivity of PTEN downstream target 88 AKT increases anoikis resistance (6-8). On the other hand, recent studies in other 89cancer types indicate for a very delicate balance between nuclear lamina stiffness and 90 anchorage-independence, anoikis resistance, and cell migration. Whereas cell 91 migration in three dimensional contexts requires a sufficiently deformable nuclear 92 lamina to allow passage through physical restrictions (9-11), too deformable nuclei may limit cancer cell survival especially in anchorage-independent conditions (9, 12-94 15). Of nuclear lamina proteins, particularly inhibition of both Lamin-A/C and Lamin-95