Pim1 Kinase Synergizes with C-MYC to Induce Advanced Prostate Carcinoma

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2010 Feb 9

PMID 20140016

Citations 80

Authors

J Wang

J Kim

M Roh

O E Franco

S W Hayward

M L Wills

S A Abdulkadir

Affiliations

Soon will be listed here.

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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References

di SantAgnese P, de Mesy Jensen K . Neuroendocrine differentiation in prostatic carcinoma. Hum Pathol. 1987; 18(8):849-56. DOI: 10.1016/s0046-8177(87)80060-6. View

Shappell S, Thomas G, Roberts R, Herbert R, Ittmann M, Rubin M . Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Res. 2004; 64(6):2270-305. DOI: 10.1158/0008-5472.can-03-0946. View

Zhang Y, Wang Z, Li X, Magnuson N . Pim kinase-dependent inhibition of c-Myc degradation. Oncogene. 2008; 27(35):4809-19. DOI: 10.1038/onc.2008.123. View

Kaplan-Lefko P, Chen T, Ittmann M, Barrios R, Ayala G, Huss W . Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate. 2003; 55(3):219-37. DOI: 10.1002/pros.10215. View

van Lohuizen M, Verbeek S, Krimpenfort P, Domen J, Saris C, Radaszkiewicz T . Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell. 1989; 56(4):673-82. DOI: 10.1016/0092-8674(89)90589-8. View

Chen W, Chan D, Donald C, Lilly M, Kraft A . Pim family kinases enhance tumor growth of prostate cancer cells. Mol Cancer Res. 2005; 3(8):443-51. DOI: 10.1158/1541-7786.MCR-05-0007. View

Aho T, Sandholm J, Peltola K, Mankonen H, Lilly M, Koskinen P . Pim-1 kinase promotes inactivation of the pro-apoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site. FEBS Lett. 2004; 571(1-3):43-9. DOI: 10.1016/j.febslet.2004.06.050. View

Schmidt T, Karsunky H, Rodel B, Zevnik B, Elsasser H, Moroy T . Evidence implicating Gfi-1 and Pim-1 in pre-T-cell differentiation steps associated with beta-selection. EMBO J. 1998; 17(18):5349-59. PMC: 1170861. DOI: 10.1093/emboj/17.18.5349. View

Kim J, Eltoum I, Roh M, Wang J, Abdulkadir S . Interactions between cells with distinct mutations in c-MYC and Pten in prostate cancer. PLoS Genet. 2009; 5(7):e1000542. PMC: 2697385. DOI: 10.1371/journal.pgen.1000542. View

10.

Garabedian E, Humphrey P, Gordon J . A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells. Proc Natl Acad Sci U S A. 1998; 95(26):15382-7. PMC: 28051. DOI: 10.1073/pnas.95.26.15382. View

11.

Valdman A, Fang X, Pang S, Ekman P, Egevad L . Pim-1 expression in prostatic intraepithelial neoplasia and human prostate cancer. Prostate. 2004; 60(4):367-71. DOI: 10.1002/pros.20064. View

12.

Roh M, Gary B, Song C, Said-Al-Naief N, Tousson A, Kraft A . Overexpression of the oncogenic kinase Pim-1 leads to genomic instability. Cancer Res. 2003; 63(23):8079-84. View

13.

Bachmann M, Hennemann H, Xing P, Hoffmann I, Moroy T . The oncogenic serine/threonine kinase Pim-1 phosphorylates and inhibits the activity of Cdc25C-associated kinase 1 (C-TAK1): a novel role for Pim-1 at the G2/M cell cycle checkpoint. J Biol Chem. 2004; 279(46):48319-28. DOI: 10.1074/jbc.M404440200. View

14.

Xin L, Ide H, Kim Y, Dubey P, Witte O . In vivo regeneration of murine prostate from dissociated cell populations of postnatal epithelia and urogenital sinus mesenchyme. Proc Natl Acad Sci U S A. 2003; 100 Suppl 1:11896-903. PMC: 304104. DOI: 10.1073/pnas.1734139100. View

15.

Hu Y, Wang T, Stormo G, Gordon J . RNA interference of achaete-scute homolog 1 in mouse prostate neuroendocrine cells reveals its gene targets and DNA binding sites. Proc Natl Acad Sci U S A. 2004; 101(15):5559-64. PMC: 397422. DOI: 10.1073/pnas.0306988101. View

16.

Saris C, Domen J, Berns A . The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG. EMBO J. 1991; 10(3):655-64. PMC: 452698. DOI: 10.1002/j.1460-2075.1991.tb07994.x. View

17.

Wang Z, Bhattacharya N, Mixter P, Wei W, Sedivy J, Magnuson N . Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase. Biochim Biophys Acta. 2002; 1593(1):45-55. DOI: 10.1016/s0167-4889(02)00347-6. View

18.

Cunha G, Lung B . The possible influence of temporal factors in androgenic responsiveness of urogenital tissue recombinants from wild-type and androgen-insensitive (Tfm) mice. J Exp Zool. 1978; 205(2):181-93. DOI: 10.1002/jez.1402050203. View

19.

Roh M, Song C, Kim J, Abdulkadir S . Chromosomal instability induced by Pim-1 is passage-dependent and associated with dysregulation of cyclin B1. J Biol Chem. 2005; 280(49):40568-77. DOI: 10.1074/jbc.M509369200. View

20.

Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G . A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol. 2004; 6(4):308-18. DOI: 10.1038/ncb1110. View