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Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma

Oncogene volume 29, pages 2477–2487 (2010)Cite this article

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Abstract

The oncogenic PIM1 kinase has been implicated as a cofactor for c-MYC in prostate carcinogenesis. In this study, we show that in human prostate tumors, coexpression of c-MYC and PIM1 is associated with higher Gleason grades. Using a tissue recombination model coupled with lentiviral-mediated gene transfer we find that Pim1 is weakly oncogenic in naive adult mouse prostatic epithelium. However, it cooperates dramatically with c-MYC to induce prostate cancer within 6-weeks. Importantly, c-MYC/Pim1 synergy is critically dependent on Pim1 kinase activity. c-MYC/Pim1 tumors showed increased levels of the active serine-62 (S62) phosphorylated form of c-MYC. Grafts expressing a phosphomimetic c-MYCS62D mutant had higher rates of proliferation than grafts expressing wild type c-MYC but did not form tumors like c-MYC/Pim1 grafts, indicating that Pim1 cooperativity with c-MYC in vivo involves additional mechanisms other than enhancement of c-MYC activity by S62 phosphorylation. c-MYC/Pim1-induced prostate carcinomas show evidence of neuroendocrine (NE) differentiation. Additional studies, including the identification of tumor cells coexpressing androgen receptor and NE cell markers synaptophysin and Ascl1 suggested that NE tumors arose from adenocarcinoma cells through transdifferentiation. These results directly show functional cooperativity between c-MYC and PIM1 in prostate tumorigenesis in vivo and support efforts for targeting PIM1 in prostate cancer.

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Acknowledgements

We thank Drs Robert Matusik, Vito Quaranta, Fritz Parl and Susan Kasper for helpful discussions. This work was supported by NIH Grant CA123484 (SAA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.

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Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    J Wang, S W Hayward & S A Abdulkadir

  2. Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA

    J Kim, M Roh, M L Wills & S A Abdulkadir

  3. Department of Urology, Vanderbilt University Medical Center, Nashville, TN, USA

    O E Franco & S W Hayward

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  1. J Wang
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Correspondence to S A Abdulkadir.

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Wang, J., Kim, J., Roh, M. et al. Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma. Oncogene 29, 2477–2487 (2010). https://doi.org/10.1038/onc.2010.10

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