RESUMO
Telomerase activity has been regarded as a critical step in cellular immortalization and carcinogenesis and because of this, regulation of telomerase represents an attractive target for anti-tumor specific therapeutics. Recently, one avenue of cancer research focuses on antisense strategy to target the oncogenes or cancer driver genes, in a sequence specific fashion to down-regulate the expression of the target gene. The protein catalytic subunit, human telomerase reverse transcriptase (hTERT) and the template RNA component (hTERC) are essential for telomerase function, thus theoretically, inhibition of telomerase activity can be achieved by interfering with either the gene expression of hTERT or the hTERC of the telomerase enzymatic complex. The present study showed that phosphorothioate antisense oligonucleotide (sASO)-nuclear localization signal (NLS) peptide conjugates targeting hTERC could inhibit telomerase activity very efficiently at 5 µM concentration but less efficiently at 1 µM concentration. On the other hand, siRNA targeting hTERT mRNA could strongly suppress hTERT expression at 200 nM concentration. It was also revealed that siRNA targeting hTERT could induce telomere attrition and then irreversible arrest of proliferation of cancer cells.
Assuntos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Sinais de Localização Nuclear/química , Oligonucleotídeos Antissenso , Fosfatos/química , Telomerase/antagonistas & inibidores , Telômero/química , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática , Células HeLa , Humanos , Peptídeos/química , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Telomerase/química , Células Tumorais CultivadasRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
MicroRNAs (miRNAs) are endogenously expressed and evolutionarily conserved small non-coding RNAs, which regulate gene expression. Several studies have shown that they are involved in fundamental biological processes, such as proliferation and apoptosis. MicroRNA dysregulation plays an important role in cancer onset and progression where miRs can function as both tumor promoters (oncomiRs) or tumor suppressors by targeting numerous biomolecules that are important in carcinogenesis. MicroRNA molecules are already entering the clinic as diagnostic and prognostic biomarkers for patient stratification and also as therapeutic targets and agents. Their role as biomarkers and therapeutic targets is appealing but several obstacles have as yet limited our ability to translate this potential into a clinical reality. This review provides a comprehensive overview of miRNAs with established functional relevance in cancer. Furthermore, approaches towards therapeutic miRNA-based intervention are discussed. Those include viral or non-viral approaches of miRNA replacement therapy in the case of tumor-suppressing miRNAs and strategies for the inhibition of oncogenic miRNAs.