title: Genetic ablation of PKC epsilon inhibits prostate cancer development and metastasis in transgenic mouse model of prostate adenocarcinoma.
abstract: Protein kinase C epsilon (PKCε), a novel PKC isoform, is overexpressed in prostate cancer (PCa) and correlates with disease aggressiveness. However, the functional contribution of PKCε to development or progression of PCa remained to be determined. Here we present the first in vivo genetic evidence that PKCε is essential for both the development and metastasis of PCa in the transgenic mouse model of prostate adenocarcinoma (TRAMP). Heterozygous or homozygous genetic deletions of PKCε in FVB/N TRAMP inhibited PCa development and metastasis as analyzed by positron emission tomography/computed tomography, tumor weight determinations, and histopathology. We also examined biomarkers associated with tumor progression in this model, including markers of survival, proliferation, angiogenesis, inflammation, and metastatic progression. To find clues about the genes regulated by PKCε and linked to the Stat3 signaling pathway, we carried out focused PCR arrays of JAK/STAT signaling in excised PCa tissues from PKCε wild-type and nullizygous TRAMP mice. Notably, PKCε loss was associated with significant downregulation of proliferative and metastatic genes C/EBPβ (CCAAT/enhancer binding protein β), CRP (C-reactive protein), CMK, EGFR (epidermal growth factor receptor), CD64, Jun B, and gp130. Taken together, our findings offer the first genetic evidence of the role of PKCε in PCa development and metastasis. PKCε may be potential target for prevention and/or treatment of PCa.
authors.affiliation: Department of Human Oncology, Wisconsin Institute of Medical Research, Paul Carbone Comprehensive Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin 53792, USA.
authors.forename: Bilal Bin
authors.initials: BB
authors.lastname: Hafeez
authors.forename: Weixiong
authors.initials: W
authors.lastname: Zhong
authors.forename: Jamey
authors.initials: J
authors.lastname: Weichert
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Dreckschmidt
authors.forename: Mohammad Sarwar
authors.initials: MS
authors.lastname: Jamal
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Verma
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002097:C-Reactive Protein / Q000235:genetics; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D015151:Immunoblotting; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D049268:Positron-Emission Tomography; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D002097:C-Reactive Protein; D066246:ErbB Receptors; D053612:Janus Kinases; D051744:Protein Kinase C-epsilon