Simultaneous targeting of androgen receptor (AR) and MAPK-interacting kinases (MNKs) by novel retinamides inhibits growth of human prostate cancer cell lines
| Autor: | Lalji K. Gediya, Andrew K. Kwegyir-Afful, Vidya P. Ramamurthy, Senthilmurugan Ramalingam, Vincent C. O. Njar |
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| Rok vydání: | 2014 |
| Předmět: |
Male
MAPK/ERK pathway medicine.medical_specialty Neoplasms Hormone-Dependent Time Factors Cell cycle checkpoint MNK Antineoplastic Agents Apoptosis Tretinoin Protein Serine-Threonine Kinases Biology Transfection Prostate cancer Cell Movement Cell Line Tumor androgen receptor Internal medicine medicine Humans Protein Kinase Inhibitors Cell Proliferation Dose-Response Relationship Drug Cell growth Kinase EIF4E Intracellular Signaling Peptides and Proteins Prostatic Neoplasms Androgen Antagonists Cell Cycle Checkpoints prostate cancer medicine.disease 3. Good health Gene Expression Regulation Neoplastic novel retinamides Androgen receptor Prostatic Neoplasms Castration-Resistant Eukaryotic Initiation Factor-4E Endocrinology Oncology Receptors Androgen eIF4E Cancer research RNA Interference Signal transduction human activities Signal Transduction Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.3084 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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