Genetic Ablation of PKC Epsilon Inhibits Prostate Cancer Development and Metastasis in Transgenic Mouse Model of Prostate Adenocarcinoma

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 6; pp. 2318 - 2327
• Main Authors: HAFEEZ, Bilal Bin, WEIXIONG ZHONG, WEICHERT, Jamey, DRECKSCHMIDT, Nancy E, MOHAMMAD SARWAR JAMAL, VERMA, Ajit K
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.03.2011
• Subjects: Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Angiogenesis; Animal models; Animals; Antineoplastic agents; Biological and medical sciences; biomarkers; C-reactive protein; C-Reactive Protein - genetics; CCAAT/enhancer-binding protein; Computed tomography; Disease Models, Animal; Epidermal growth factor receptors; Female; Gene deletion; Gene Expression; Glycoprotein gp130; Gynecology. Andrology. Obstetrics; Humans; Immunoblotting; Janus Kinases - metabolism; Male; Male genital diseases; Medical sciences; Metastases; Mice; Mice, Knockout; Mice, Transgenic; Neoplasm Metastasis; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Polymerase chain reaction; Positron emission tomography; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein kinase C; Protein Kinase C-epsilon - genetics; Protein Kinase C-epsilon - metabolism; Receptor, Epidermal Growth Factor - genetics; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stat3 protein; STAT3 Transcription Factor - metabolism; Tomography, X-Ray Computed; Transgenic mice; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Animal model; Protein kinase C; Urinary system disease; Prostate disease; Enzyme; Transferases; Rodentia; Transgenic animal; Malignant tumor; Metastasis; Prostate adenocarcinoma; Carcinogenesis; Vertebrata; Mammalia; Mouse; Genetics; Inhibitor; Male genital diseases; Prostate cancer; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-4170

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.