Rupp, C., Isomursu, A., Aakula, A., Erickson, A., Li, S. P., Kaur, A., Shah, P., Pokharel, Y. R., Trottman, L., Lammerding, J., Rannikko, A., Taimen, P., Mirtti, T., Paatero, I., Ivaska, J., Westermarck, J. K. (July 2019) Combined inhibition of tumor suppressors PTEN and PP2A drives anoikis resistance and is associated with therapy relapse in prostate cancer. Cancer Research, 79 (13S). Meeting Abstract: 3486 . ISSN 0008-5472
Abstract
Reactivation of tumor suppressor phosphatases may provide entirely novel opportunities for cancer therapy. Here, we discover clinically relevant functional co-operation between loss of activities of two human tumor suppressor phosphatases, PTEN, and PP2A. Analysis of prostate cancer tissue microarray material consisting of 358 patients treated primarily with radical prostatectomy revealed that overexpression of PP2A inhibitor protein PME-1 associates with significantly shorter time to therapy relapse in patients with PTEN-deficient PrCa. Further, PP2A inhibition by PME-1 overexpression in PTEN-deficient cell models inhibits apoptosis induction in anchorage-independent conditions (anoikis). PP2A reactivation by small molecules (SMAPs) was also found to inhibit viability of PTEN-deficient PrCa cells. Importantly, rather than regulating the well-known PP2A target pathways, PME-1 was found to physically associate with, and to regulate deformability of the nuclear lamina in PrCa cells. Mass spectrometry phosphoproteomics analysis identified several PME-1-regulated nuclear lamina constituents, and PME-1 deficient cells with compromised nuclear lamina were particularly vulnerable to apoptosis induction by mechanical stress. As a direct molecular target, Lamin A/C phosphorylation was found to be protected by PME-1-mediated PP2A inhibition under anoikis-inducing conditions. PME-1 inhibition in PrCa cells resulted in increased apoptosis in an in ovo tumor model, and PME-1-depleted cells had compromised long-term survival in zebrafish circulation. In summary we discover that PP2A reactivation by PME-1 targeting sensitizes PTEN-deficient PrCa cells to anoikis. Clinically, the results identify PME-1 as a novel candidate biomarker for increased relapse risk in PTEN-deficient PrCa, and indicate pharmacological PP2A activation as a novel potential therapeutic approach against circulating prostate cancer cells. At the general level, the results clearly emphasize the need for better understanding of phosphatases as key modulators of cancer progression. Citation Format: Christian Rupp, Aleksi Isomursu, Anna Aakula, Andrew Erickson, Song-Ping Li, Amanpreet Kaur, Pragya Shah, Yuba R. Pokharel, Lloyd Trottman, Jan Lammerding, Antti Rannikko, Pekka Taimen, Tuomas Mirtti, Ilkka Paatero, Johanna Ivaska, Jukka K. Westermarck. Combined inhibition of tumor suppressors PTEN and PP2A drives anoikis resistance and is associated with therapy relapse in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3486
| Item Type: | Paper |
|---|---|
| Additional Information: | Meeting Abstract |
| Subjects: | organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell signaling diseases & disorders > cancer > cancer types > prostate cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein phosphatase |
| CSHL Authors: | |
| Communities: | CSHL labs > Trotman lab |
| Depositing User: | Matthew Dunn |
| Date: | July 2019 |
| Date Deposited: | 08 Nov 2019 18:14 |
| Last Modified: | 08 Nov 2019 18:14 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/38644 |
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