BIRC6 Targeting as Potential Therapy for Advanced, Enzalutamide-Resistant Prostate Cancer
| Autor: | Rebecca Wu, Hui Xue, Martin E. Gleave, Raunak Shrestha, Peter W. Gout, Yuwei Wang, Yuzhuo Wang, Dong Lin, Iris Sze Ue Luk, Amina Zoubeidi, Anne Haegert, Xin Dong, Fang Zhang, Colin Collins |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Cancer Drug resistance Biology Bioinformatics Inhibitor of apoptosis medicine.disease Androgen receptor Gene expression profiling 03 medical and health sciences chemistry.chemical_compound Prostate cancer 030104 developmental biology 0302 clinical medicine Oncology chemistry 030220 oncology & carcinogenesis medicine Cancer research Enzalutamide Growth inhibition |
| Zdroj: | Clinical Cancer Research. 23:1542-1551 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Enzalutamide resistance has emerged as a major problem in the management of castration-resistant prostate cancer (CRPC). Research on therapy resistance of CRPCs has primarily focused on the androgen receptor pathway. In contrast, there is limited information on antiapoptotic mechanisms that may facilitate the treatment resistance. The inhibitor of apoptosis proteins (IAP) family is well recognized for its role in promoting treatment resistance of cancers by inhibiting drug-induced apoptosis. Here, we examined whether BIRC6, an IAP family member, has a role in enzalutamide resistance of CRPCs and could provide a therapeutic target for enzalutamide-resistant CRPC. Experimental Design: Use of enzalutamide-resistant CRPC models: (i) the transplantable, first high-fidelity LTL-313BR patient-derived enzalutamide-resistant CRPC tissue xenograft line showing primary enzalutamide resistance, (ii) MR42D and MR49F CRPC cells/xenografts showing acquired enzalutamide resistance. Specific BIRC6 downregulation in these models was produced using a BIRC6-targeting antisense oligonucleotide (ASO-6w2). Gene expression was determined by qRT-PCR and gene expression profiling. Molecular pathways associated with growth inhibition were assessed via gene enrichment analysis. Results: Of eight IAPs examined, BIRC6 was the only one showing elevated expression in both enzalutamide-resistant CRPC models. Treatment with ASO-6w2 markedly suppressed growth of LTL-313BR xenografts and increased tumor apoptosis without inducing major host toxicity. Pathway enrichment analysis indicated that GPCR and matrisome signaling were the most significantly altered pathways. Furthermore, ASO-6w2 inhibited expression of prosurvival genes that were upregulated in the LTL-313BR line. Conclusions: BIRC6 targeting inhibited the growth of enzalutamide-resistant CRPC models and may represent a new option for clinical treatment of advanced, enzalutamide-resistant prostate cancer. Clin Cancer Res; 23(6); 1542–51. ©2016 AACR. |
| Databáze: | OpenAIRE |
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