Hong Yin1, Mary Lowery, Jonathan Glass. 1. Department of Medicine, Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, Louisiana 71130-3932, USA. hyin@lsuhsc.edu
Abstract
BACKGROUND: The CCAAT/Enhancer binding protein alpha (C/EBPalpha) is an important transcription factor for granulopoiesis and adipogenesis. While decreased expression and mutation of C/EBPalpha has been found in several types of tumors, the role of C/EBPalpha in prostate cancer has not been well characterized. METHODS: We quantitatively analyzed the immunochemical staining of prostate cancer tissue and examined the growth properties of prostate cancer cells stably expressing C/EBPalpha by measure growth curve, cell cycle, and anchorage independent colony formation, investigated the association of C/EBPalpha with E2Fs and CDKs by co-immunoprecipitation and examined the expression of CDKs and activation of AKT by Western blot analysis. RESULTS: The ratio of C/EBPalpha expression between cancer cells close to the pseudolumen of glands and those nearer the basal cell layer was more than threefold greater than that seen in the normal prostate epithelium. Further, this ratio increased with increased Gleason score of the prostate cancer. Forced expression of C/EBPalpha in prostate cancer cell lines accelerated cell growth, stimulated cells into the S and G2 phases of cell cycle, and enhanced anchorage-independent colony formation. Simultaneously, forced expression of C/EBPalpha increased expression of CDK2/CDK4 and nuclear PP2A, and activated AKT. In addition, C/EBPalpha was no longer found associated with E2F1/E2F4 and CDK2/CDK4. AKT and PPA2 inhibitors restored both the anti-proliferation function of C/EBPalpha and the interaction between C/EBPalpha and E2F1/E2F4. CONCLUSION: In prostate cancer cells C/EBPalpha cannot function as a tumor suppressor.
BACKGROUND: The CCAAT/Enhancer binding protein alpha (C/EBPalpha) is an important transcription factor for granulopoiesis and adipogenesis. While decreased expression and mutation of C/EBPalpha has been found in several types of tumors, the role of C/EBPalpha in prostate cancer has not been well characterized. METHODS: We quantitatively analyzed the immunochemical staining of prostate cancer tissue and examined the growth properties of prostate cancer cells stably expressing C/EBPalpha by measure growth curve, cell cycle, and anchorage independent colony formation, investigated the association of C/EBPalpha with E2Fs and CDKs by co-immunoprecipitation and examined the expression of CDKs and activation of AKT by Western blot analysis. RESULTS: The ratio of C/EBPalpha expression between cancer cells close to the pseudolumen of glands and those nearer the basal cell layer was more than threefold greater than that seen in the normal prostate epithelium. Further, this ratio increased with increased Gleason score of the prostate cancer. Forced expression of C/EBPalpha in prostate cancer cell lines accelerated cell growth, stimulated cells into the S and G2 phases of cell cycle, and enhanced anchorage-independent colony formation. Simultaneously, forced expression of C/EBPalpha increased expression of CDK2/CDK4 and nuclear PP2A, and activated AKT. In addition, C/EBPalpha was no longer found associated with E2F1/E2F4 and CDK2/CDK4. AKT and PPA2 inhibitors restored both the anti-proliferation function of C/EBPalpha and the interaction between C/EBPalpha and E2F1/E2F4. CONCLUSION: In prostate cancer cells C/EBPalpha cannot function as a tumor suppressor.
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