retinamide and Prostatic-Neoplasms--Castration-Resistant

Topics: Alternative Splicing; Animals; Antineoplastic Agents; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Male; Mice; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Protein Serine-Threonine Kinases; Receptors, Androgen; RNA Interference; Signal Transduction; Tretinoin; Xenograft Model Antitumor Assays

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.

Topics: Androgen Antagonists; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Eukaryotic Initiation Factor-4E; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Receptors, Androgen; RNA Interference; Signal Transduction; Time Factors; Transfection; Tretinoin