Simultaneous targeting of androgen receptor (AR) and MAPK-interacting kinases (MNKs) by novel retinamides inhibits growth of human prostate cancer cell lines
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Vidya P. Ramamurthy1,2, Senthilmurugan Ramalingam1,2, Lalji Gediya1,2, Andrew K. Kwegyir-Afful1,2 and Vincent C.O. Njar1,2,3
1 Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA
2 Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA
3 Marlene Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
Vincent C.O. Njar, email:
Keywords: androgen receptor, eIF4E, MNK, novel retinamides, prostate cancer
Received: July 23, 2014 Accepted: December 23, 2014 Published: December 26, 2014
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.
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