Nowak, D. G., Cho, H., Herzka, T., Wang, V. M. Y., Senturk, S., DeMarco, D. V., Ding, D., Fellmann, C., Beinortas, T., Kleinman, D., Watrud, K., Chen, M., Wilkinson, J. E., Castillo-Martin, M., Cordon-Cardo, C., Robinson, B. D., Trotman, L. C. (August 2015) Myc drives Pten/ p53-deficient proliferation and metastasis due to Il6-secretion and Akt-suppression via Phlpp2. Cancer Research, 75 (Supple). Abstract 2258. ISSN 0008-5472
Abstract
The sporadic transition from indolent to metastatic disease is a hallmark of prostate cancer (PC) and frequently involves deletion of PTEN and TP53. We recently recapitulated metastasis of Pten/ Trp53-mutant PC in mouse using the RapidCaP system and surprisingly, we found that it is driven by Myc, rather than Akt activation. Here, we show that cell-cell communication by Il6 drives this Akt-Myc switch through activation of the Akt-inactivating phosphatase Phlpp2. Primary cells revealed that loss of Pten/ Trp53 triggers secretion of the Il6 cytokine when these genes are deleted together, but not separately. Il6 then communicates a downstream program of Stat3-mediated Myc activation, which drives cell proliferation. Abrogation of Myc activity by Myc inhibition with the JQ1 bromodomain inhibitor, Myc-RNAi, and Myc-CRISPR/ Cas9 approaches inhibited proliferation. We validated these findings in vivo, where peak proliferation in Pten/ Trp53 mutant primary and metastatic PC did not correlate with activated Akt, but with Stat3/ Myc activation instead. Most notably, we found that Myc strongly activates the Akt phosphatase Phlpp2 in primary cells and RapidCaP metastasis, and showed genetically that Phlpp2 is essential for dictating proliferation and Myc-mediated suppression of Akt. Collectively, our data reveal competition between two proto-oncogenes: Myc and Akt, which ensnarls the Phlpp2 gene to facilitate Myc-driven metastasis.
| Item Type: | Paper |
|---|---|
| Additional Information: | Meeting Abstract |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Akt diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > Myc bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation Publication Type > Meeting Abstract diseases & disorders > cancer > metastasis |
| CSHL Authors: | |
| Communities: | CSHL labs > Trotman lab |
| Depositing User: | Matt Covey |
| Date: | August 2015 |
| Date Deposited: | 01 Apr 2016 20:20 |
| Last Modified: | 06 Feb 2018 15:10 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/32474 |
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