title: Cell type-specific abundance of 4EBP1 primes prostate cancer sensitivity or resistance to PI3K pathway inhibitors.
abstract: Pharmacological inhibitors against the PI3K-AKT-mTOR (phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) pathway, a frequently deregulated signaling pathway in cancer, are clinically promising, but the development of drug resistance is a major limitation. We found that 4EBP1, the central inhibitor of cap-dependent translation, was a critical regulator of both prostate cancer initiation and maintenance downstream of mTOR signaling in a genetic mouse model. 4EBP1 abundance was distinctly different between the epithelial cell types of the normal prostate. Of tumor-prone prostate epithelial cell types, luminal epithelial cells exhibited the highest transcript and protein abundance of 4EBP1 and the lowest protein synthesis rates, which mediated resistance to both pharmacologic and genetic inhibition of the PI3K-AKT-mTOR signaling pathway. Decreasing total 4EBP1 abundance reversed resistance in drug-insensitive cells. Increased 4EBP1 abundance was a common feature in prostate cancer patients who had been treated with the PI3K pathway inhibitor BKM120; thus, 4EBP1 may be associated with drug resistance in human tumors. Our findings reveal a molecular program controlling cell type-specific 4EBP1 abundance coupled to the regulation of global protein synthesis rates that renders each epithelial cell type of the prostate uniquely sensitive or resistant to inhibitors of the PI3K-AKT-mTOR signaling pathway.
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA. Division of Hematology/Oncology and Department of Internal Medicine, University of California, San Francisco, San Francisco, CA 94158, USA. ahsieh@fredhutch.org davide.ruggero@ucsf.edu.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Hsieh
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Hao G
authors.initials: HG
authors.lastname: Nguyen
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Lexiaochuan
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Merritt P
authors.initials: MP
authors.lastname: Edlind
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Carroll
authors.affiliation: Division of Hematology/Oncology and Department of Internal Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Won
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. ahsieh@fredhutch.org davide.ruggero@ucsf.edu.
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D012333:RNA, Messenger; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases