Targeting post-transcriptional control for drug discovery

Peltz, Stuart W.; Welch, Ellen; Trotta, Christopher R.; Davis, Thomas W.; Jacobson, Allan

doi:10.4161/rna.6.3.8953

Cited by 16 publications

(12 citation statements)

References 63 publications

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“…These observations allowed the construction of a platform to identify compounds impacting the regulatory mechanisms within the BMI-1 5‘UTR and 3‘UTR to modulate BMI-1 protein expression (14, 20). …”

Section: Resultsmentioning

confidence: 99%

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BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer

Bansal

Bartucci

Yusuff

et al. 2016

Clinical Cancer Research

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Purpose Current prostate cancer (PCa) management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy-resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TICs-tailored therapies appears to be a promising approach. Experimental design We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient derived prostate cancer cells and xenograft models to characterize the effects of pharmacological inhibitors of BMI-1. Results We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacological inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor (AR)-directed therapies, without toxic effects on normal tissues. Conclusions Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective PCa treatment.

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Section: Resultsmentioning

confidence: 99%

“…A high-throughput screen against a library of >200,000 small molecules (PTC Therapeutics) identified seven compounds targeting the post-transcriptional control mechanisms described above (14, 20). To examine their antitumor activity, we determined their IC 50 concentrations in DU145 cells (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer

Bansal

Bartucci

Yusuff

et al. 2016

Clinical Cancer Research

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“…Optimizing the tunnel-bound antibiotics for inhibiting specific proteins may increase the cidality of the drugs, thereby improving the outcomes of antibiotic therapy. Furthermore, identifying small molecules that modulate the translation of individual proteins in the eukaryotic cell by binding in the NPET of the eukaryotic ribosome can find application in broad areas of medicine (Peltz et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Selective Protein Synthesis by Ribosomes with a Drug-Obstructed Exit Tunnel

Kannan

Vázquez‐Laslop

Mankin

2012

Cell

132

157

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The polypeptide exit tunnel is an important functional compartment of the ribosome where the newly synthesized proteins are surveyed. The tunnel is the target of clinically important macrolide antibiotics. Macrolides plug the tunnel and are believed to stop production of all proteins. Contrary to this view, we show that drug-bound ribosomes can synthesize a distinct subset of cellular polypeptides. The structure of a protein defines its ability to thread through the antibiotic-obstructed tunnel. Synthesis of certain polypeptides that initially bypass translational arrest can be stopped at later stages of elongation while translation of some proteins goes to completion. Our findings reveal that small-molecule effectors can accentuate the discriminatory properties of the ribosomal exit tunnel and that macrolide antibiotics reshape the cellular proteome rather than block global protein synthesis.

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“…It has become increasingly understood over the last decade that appropriate expression of many genes requires extensive posttranscriptional control [Peltz et al, 2009]. The main steps in posttranscriptional regulation are: RNA processing and maturation, RNA transport/subcellular localization; mRNA translation; and mRNA degradation.…”

Section: Post-transcriptional Regulation Of Bmi1 Expressionmentioning

confidence: 99%

BMI1 as a novel target for drug discovery in cancer

et al. 2011

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Growing evidence has demonstrated that clonogenic cancer stem (initiating) cells are responsible for tumor regrowth and disease relapse. Bmi-1 plays a critical role in the self-renewal of adult stem cells. The Bmi-1 protein is elevated in many types of cancers, and experimental reduction of Bmi-1 protein levels by small interfering RNA (siRNA) causes apoptosis and/or senescence in tumor cells in vitro and increases susceptibility to cytotoxic agents. The Bmi-1 protein has no known enzymatic activity, but serves as the key regulatory component of the PRC1 complex (polycomb repressive complex-1). This complex influences chromatin structure and regulates transcriptional activity of a number of important loci including the Ink4a locus which encodes the tumor suppressor proteins p16(Ink4a) and p14(Arf) . In this prospective study, we will discuss the implication of BMI1 in cancers, the biology of BMI1, and the regulatory control of BMI1 expression. The target validation and the future prospects of targeting BMI1 in cancer therapy are also discussed.

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Targeting post-transcriptional control for drug discovery

Cited by 16 publications

References 63 publications

BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer

BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer

Selective Protein Synthesis by Ribosomes with a Drug-Obstructed Exit Tunnel

BMI1 as a novel target for drug discovery in cancer

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