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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.

SUBMITTER: Ramamurthy VP

PROVIDER: S-EPMC4413647 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Simultaneous targeting of androgen receptor (AR) and MAPK-interacting kinases (MNKs) by novel retinamides inhibits growth of human prostate cancer cell lines.

Ramamurthy Vidya P VP Ramalingam Senthilmurugan S Gediya Lalji L Kwegyir-Afful Andrew K AK Njar Vincent C O VC

Oncotarget 20150201 5

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 proliferatio ...[more]

PMID: 25605250

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Project description:BACKGROUND:Sirtuin-7 (SIRT7) is associated with the maintenance of tumorigenesis. However, its functional roles and oncogenic mechanisms in prostate cancer (PCa) are poorly understood. Here, we investigated the roles and underlying molecular mechanisms of SIRT7 in PCa cell growth and androgen-induced autophagy. METHODS:The LNCap and 22Rv1 PCa cell lines were subjected to quantitative reverse transcription (RT)-PCR to characterize their genes encoding SIRT7, AR, and SMAD4. The proteins produced from these genes were quantified by western blotting and immunoprecipitation analysis. SIRT7-depleted cells were produced by transfection with plasmid vectors bearing short hairpin RNAs against SIRT7. The proliferation of each cell line was assessed by CCK8 and EdU assays. Autophagic flux was tracked by mRFP-GFP-LC3 adenovirus under an immunofluorescence microscope. Apoptosis was evaluated by flow cytometry. Tumors were induced in mouse axillae by injection of the cell lines into mice. Tumor morphology was examined by immunohistochemistry and relative tumor growth and metastases were compared by a bioluminescence-based in vivo imaging system. RESULTS:SIRT7 depletion significantly inhibited cell proliferation, androgen-induced autophagy, and invasion in LNCap and 22Rv1 cells (in vitro) and mouse xenograft tumors induced by injection of these cells (in vivo). SIRT7 knockdown also increased the sensitivity of PCa cells to radiation. Immunohistochemical analysis of 93 specimens and bioinformatic analysis revealed that SIRT7 expression was positively associated with androgen receptor (AR). Moreover, the AR signal pathway participated in SIRT7-mediated regulation of PCa cell proliferation, autophagy, and invasion. SIRT7 depletion downregulated the AR signal pathway by upregulating the level of SMAD4 protein in PCa cells. CONCLUSION:SIRT7 plays an important role in the development and progression of human PCa and may be a promising prognostic marker for prostate cancer.

Dataset Information

Simultaneous targeting of androgen receptor (AR) and MAPK-interacting kinases (MNKs) by novel retinamides inhibits growth of human prostate cancer cell lines.

Publications

Simultaneous targeting of androgen receptor (AR) and MAPK-interacting kinases (MNKs) by novel retinamides inhibits growth of human prostate cancer cell lines.

Similar Datasets

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