TY - JOUR
T1 - MYC drives Pten/Trp53-deficient proliferation and metastasis due to IL6 secretion and AKT suppression via PHLPP2
AU - Nowak, Dawid G.
AU - Cho, Hyejin
AU - Herzka, Tali
AU - Watrud, Kaitlin
AU - Demarco, Daniel V.
AU - Wang, Victoria M.Y.
AU - Senturk, Serif
AU - Fellmann, Christof
AU - Ding, David
AU - Beinortas, Tumas
AU - Kleinman, David
AU - Chen, Muhan
AU - Sordella, Raffaella
AU - Wilkinson, John E.
AU - Castillo-Martin, Mireia
AU - Cordon-Cardo, Carlos
AU - Robinson, Brian D.
AU - Trotman, Lloyd C.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84932634178&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-14-1113
DO - 10.1158/2159-8290.CD-14-1113
M3 - Article
C2 - 25829425
AN - SCOPUS:84932634178
SN - 2159-8274
VL - 5
SP - 637
EP - 651
JO - Cancer Discovery
JF - Cancer Discovery
IS - 6
ER -