Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma.
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.
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
J
J
Wang
J
J
Kim
M
M
Roh
O E
OE
Franco
S W
SW
Hayward
M L
ML
Wills
S A
SA
Abdulkadir
D000230:Adenocarcinoma / Q000209:etiology; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018358:Neuroendocrine Tumors / Q000473:pathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000502:physiology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000032:analysis / Q000502:physiology*
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051573:Proto-Oncogene Proteins c-pim-1