MicroRNA-24 regulates XIAP to reduce the apoptosis threshold in cancer cells

Abstract

MicroRNAs have been implicated as important mediators of cancer cell homeostasis, and accumulating data suggest compelling roles for them in the apoptosis pathway. X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor and an important barrier to apoptotic cell death, but the mechanisms which determine the diverse range of XIAP expression seen in cancer remains unclear. In this study, we present evidence that miR-24 directly targets the 3′UTR of the XIAP mRNA to exert translational repression. Using a heuristic algorithm of bioinformatics analysis and in vitro screening, we identified miR-24 as a candidate regulator of XIAP expression. Array CGH and SKY analysis reveal that genomic copy number loss at the miR-24 locus is concordant with loss of endogenous miR-24 in cancer cells. Using a luciferase construct of the XIAP 3′UTR, we showed that miR-24 specifically coordinates to the XIAP mRNA. And interference with miR-24’s binding of the critical seed region, resulting from site-directed mutagenesis of the 3′UTR, significantly abrogated miR-24’s effects on XIAP expression. Moreover, miR-24 over-expression can overcome apoptosis-resistance in cancer cells via down-regulation of XIAP expression, and the resulting cancer cell death induced by TRAIL is executed by the canonical caspase-mediated apoptosis pathway. In summary, our data suggest a novel mechanism by which miR-24 directly modulates XIAP expression level and consequently the apoptosis threshold in cancer cells.

miR-634 Activates the Mitochondrial Apoptosis Pathway and Enhances Chemotherapy-Induced Cytotoxicity

“…The ability of tumor cells to acquire chemoresistance is known to be via activation of cytoprotective processes against apoptosis, and therapeutically targeting these processes may be effective in overcoming chemoresistance (11)(12)(13). Our group as well as others has identified several miRNAs that can directly target cytoprotective processes, including the antiapoptosis pathway (XIAP, BIRC5), antioxidant activity (NRF2), and autophagy (ATG4, ATG7), and demonstrated that enforced expression of these miRNAs promotes drug-induced apoptosis in several human cancers (10,(37)(38)(39)(40)(41)(42)(43). On the other hand, clinical trials for miRNA therapy of liver and malignant hematopoietic cancers using a synthetic miR-34a mimic are currently ongoing (44,45).…”

Influence of miRNA-106b and miRNA-135a on butyrate-regulated expression of p21 and Cyclin D2 in human colon adenoma cells

“…Therefore, we conclude that histone deacetylation has no or only minor effects on miR-24 expression. Xie et al (2013) also demonstrated that miR-24 expression is not altered by treatment with TSA or DAC (5-aza-20-deoxycytidine).…”

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

“…Later on, the same group [135] demonstrated that miR-34a and miR-34c, which are downregulated in NSCLC cell lines, could play a significant role in lung carcinogenesis by modulating the expression of PDGFR-α/β and thereby regulating TRAIL-induced cell death sensitivity. Another miRNA that can be involved in TRAIL resistance is miR-24 [136]. This miRNA directly downregulates the expression of XIAP and induces sensitivity to TRAIL-based therapy in TRAILresistant lung cancer cell line.…”