The oncogenic PIM1 kinase has been implicated as a cofactor for the oncogene c-MYC in prostate carcinogenesis. In this study, we show that co-expression of c-MYC and PIM1 is associated with high Gleason grade in prostate cancer. Using a tissue recombination model coupled with lentiviral-mediated gene transfer we show 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 and Pim1 synergy is critically dependent on Pim1 kinase activity. c-MYC/Pim1 expressing tumors showed increased phosphorylation of MYC on serine 62. Expression of a phosphomimetic c-MYC S62D mutant resulted in higher rates of proliferation compared to that of wild type c-MYC. However, c-MYC S62D did not result in tumors like c-MYC/Pim1 grafts, indicating that Pim1 cooperativity with c-MYC involves additional mechanisms other than enhancement of c-MYC activity by S62 phosphorylation. In addition, c-MYC/Pim1-induced prostate carcinomas demonstrate evidence of neuroendocrine (NE) differentiation. Additional studies, including the identification of tumor cells co-expressing androgen receptor and NE cell markers synaptophysin and Ascl1 suggest that NE tumors arise from adenocarcinoma cells through transdifferentiation. These results directly demonstrate functional cooperation between c-MYC and Pim1 in prostate tumorigenesis in vivo and support therapeutic strategies for targeting PIM1 in prostate cancer.
Since Pim1 deficiency is well tolerated in vivo, it has been proposed that Pim1 inhibition may offer an attractive option to impede prostate cancer progression. In the current study, we used small hairpin interfering RNA (shRNA) directed against Pim1 to determine the anti-tumor effects in prostate cancer cell lines. In mouse c-MYC/Pim1 prostate tumor-derived cells and human prostate cancer cells, Pim1 knockdown markedly decreased cellular proliferation, survival, and tumorigenicity. Further studies indicate that in prostate cancer cells, Pim1 is required to maintain ERK/MAPK signaling pathway activation. Thus, Pim1 is necessary to maintain tumorigenicity, and may represent an efficient target for prostate cancer therapy.
(Note: Human MYC and mouse Pim1 are cloned in lentiviral constructs and used for this study)
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12042010-030217 |
| Date | 22 December 2010 |
| Creators | Wang, Jie |
| Contributors | Vito Quaranta, Simon Hayward, Robert Matusik, Fritz Parl, Sarki Abdulkadir |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-12042010-030217/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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