title: Simultaneous targeting of androgen receptor (AR) and MAPK-interacting kinases (MNKs) by novel retinamides inhibits growth of human prostate cancer cell lines.
abstract: Androgen receptor (AR) and MNK activated eIF4E signaling promotes the development and progression of prostate cancer (PCa). In this study, we report that our Novel Retinamides (NRs) target both AR signaling and eIF4E translation in androgen sensitive and castration resistant PCa cells via enhancing AR and MNK degradation through ubiquitin-proteasome pathway. Dual blockade of AR and MNK initiated eIF4E activation by NRs in turn induced cell cycle arrest, apoptosis, and inhibited cell proliferation. NRs also inhibited cell migration and invasion in metastatic cells. Importantly, the inhibitory effects of NRs on AR signaling, eIF4E translation initiation and subsequent oncogenic program were more potent than that observed with clinically relevant retinoids, established MNK inhibitors, and the FDA approved PCa drugs. Our findings provide the first preclinical evidence that simultaneous inhibition of AR and eIF4E activation is a novel and efficacious therapeutic approach for PCa, and that NRs hold significant promise for treatment of advanced prostate cancer.
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Vidya P
authors.initials: VP
authors.lastname: Ramamurthy
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Senthilmurugan
authors.initials: S
authors.lastname: Ramalingam
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Lalji
authors.initials: L
authors.lastname: Gediya
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Kwegyir-Afful
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA.|Marlene Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen; D014212:Tretinoin; C054441:retinamide; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases