Accession Number : ADA621015


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


Descriptive Note : Annual rept. 5 Jul 2014-4 Jul 2015


Corporate Author : JOHNS HOPKINS UNIV BALTIMORE MD


Personal Author(s) : Barakat, David J ; Denmeade, Samuel R ; Friedman, Alan D


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a621015.pdf


Report Date : Aug 2015


Pagination or Media Count : 29


Abstract : 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 C/EBP 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 C/EBP beta translational isoforms in prostate cancer resistance to chemotherapy. The 4E/G interaction inhibitor (4E/Gi), which blocks cap-dependent translation, significantly upregulated the LAP isoforms in both PC3 and LNCaP cells. Suppression of C/EBP beta in PC3 cells increased mTOR activity and induction of LAP expression by 4E/Gi and bicalutamide treatment additively suppressed mTOR. We also evaluated the proteasome inhibitor bortezomib as another means to alter C/EBP isoforms, because it can also inhibit cap-dependent translation. Bortezomib increased the LAP:LIP 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.


Descriptors :   *CHEMOTHERAPY , *PROSTATE CANCER , *PROTEINS , ACTIVATION , ANDROGENS , PHOSPHORUS TRANSFERASES , RECEPTOR SITES(PHYSIOLOGY) , RESISTANCE(BIOLOGY) , SENSITIVITY


Subject Categories : Biochemistry
      Medicine and Medical Research
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE