1. Myc drives Pten/p53-deficient proliferation and metastasis due to Il6-secretion and Akt-suppression via Phlpp2
- Author
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Serif Senturk, Kaitlin Watrud, Victoria M.-Y. Wang, Muhan Chen, Hyejin Cho, Daniel V. DeMarco, David Ding, Raffaella Sordella, Mireia Castillo-Martin, Tumas Beinortas, David Kleinman, Brian D. Robinson, John E. Wilkinson, Dawid G. Nowak, Christof Fellmann, Carlos Cordon-Cardo, Tali Herzka, and Lloyd C. Trotman
- Subjects
Male ,STAT3 Transcription Factor ,Lung Neoplasms ,Genotype ,Genes, myc ,Cell Communication ,Article ,Epithelium ,Metastasis ,Mice ,Neoplasms ,medicine ,Phosphoprotein Phosphatases ,PTEN ,Animals ,Humans ,Neoplasm Metastasis ,Phosphorylation ,STAT3 ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Oncogene ,biology ,Interleukin-6 ,PTEN Phosphohydrolase ,Prostatic Neoplasms ,medicine.disease ,Oncology ,Mutation ,biology.protein ,Cancer research ,Signal transduction ,Stromal Cells ,Tumor Suppressor Protein p53 ,Proto-Oncogene Proteins c-akt ,Gene Deletion ,Protein Binding ,Signal Transduction - Abstract
We have recently recapitulated metastasis of human PTEN/TP53–mutant prostate cancer in the mouse using the RapidCaP system. Surprisingly, we found that this metastasis is driven by MYC, and not AKT, activation. Here, we show that cell–cell communication by IL6 drives the AKT–MYC switch through activation of the AKT-suppressing phosphatase PHLPP2, when PTEN and p53 are lost together, but not separately. IL6 then communicates a downstream program of STAT3-mediated MYC activation, which drives cell proliferation. Similarly, in tissues, peak proliferation in Pten/Trp53–mutant primary and metastatic prostate cancer does not correlate with activated AKT, but with STAT3/MYC activation instead. Mechanistically, MYC strongly activates the AKT phosphatase PHLPP2 in primary cells and prostate cancer metastasis. We show genetically that Phlpp2 is essential for dictating the proliferation of MYC-mediated AKT suppression. Collectively, our data reveal competition between two proto-oncogenes, MYC and AKT, which ensnarls the Phlpp2 gene to facilitate MYC-driven prostate cancer metastasis after loss of Pten and Trp53. Significance: Our data identify IL6 detection as a potential causal biomarker for MYC-driven metastasis after loss of PTEN and p53. Second, our finding that MYC then must supersede AKT to drive cell proliferation points to MYC inhibition as a critical part of PI3K pathway therapy in lethal prostate cancer. Cancer Discov; 5(6); 636–51. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 565
- Published
- 2015