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Regulating Prostate Cancer Sensitivity to Chemotherapy through Translational Control of CCAAT Enhancer Binding Proteins

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Annual rept. 5 Jul 2014-4 Jul 2015

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Hyper-activation of the PI3K-AKT-mTOR signaling pathway is frequently observed in advanced prostate cancer and has been suggested to promote survival of prostate cancer cells under androgen deprivation. The transcription factor CEBP beta is expressed as three different translational isoforms from a single transcript and has been suggested to regulate mTOR activity. The longer LAP isoforms promote cell survival, growth arrest and differentiation whereas the LIP isoform can promote cell proliferation. The purpose of these studies were to evaluate the role of CEBP beta translational isoforms in prostate cancer resistance to chemotherapy. The 4EG interaction inhibitor 4EGi, which blocks cap-dependent translation, significantly upregulated the LAP isoforms in both PC3 and LNCaP cells. Suppression of CEBP beta in PC3 cells increased mTOR activity and induction of LAP expression by 4EGi and bicalutamide treatment additively suppressed mTOR. We also evaluated the proteasome inhibitor bortezomib as another means to alter CEBP isoforms, because it can also inhibit cap-dependent translation. Bortezomib increased the LAPLIP ratio in LNCaP and PC3 cells and suppression of CEBPB sensitized these cells to bortezomib in vitro. PC3 xenografts deficient in CEBPB showed suppressed growth and were also sensitized to bortezomib administration. Our data suggest that CEBPB LAP isoforms suppress AKT-mTOR activity, but may protect prostate cancer cells from bortezomib. Conversely, increasing CEBPB LAP isoform levels by blocking cap-dependent translation may be an effective strategy to prevent transition to castrate-resistant prostate cancer or sensitize prostate cancer cells to mTOR inhibitors by suppressing AKT activity.

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  • Biochemistry
  • Medicine and Medical Research
  • Pharmacology

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