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Abstract
MicroRNAs are strongly implicated in such processes as development, carcinogenesis, cell survival, and apoptosis. It is likely, therefore, that they can also modulate sensitivity and resistance to anticancer drugs in substantial ways. To test this hypothesis, we studied the pharmacologic roles of three microRNAs previously implicated in cancer biology (let-7i, mir-16, and mir-21) and also used in silico methods to test pharmacologic microRNA effects more broadly. In the experimental system, we increased the expression of individual microRNAs by transfecting their precursors (which are active) or suppressed the expression by transfection of antisense oligomers. In three NCI-60 human cancer cell lines, a panel of 60 lines used for anticancer drug discovery, we assessed the growth-inhibitory potencies of 14 structurally diverse compounds with known anticancer activities. Changing the cellular levels of let-7i, mir-16, and mir-21 affected the potencies of a number of the anticancer agents by up to 4-fold. The effect was most prominent with mir-21, with 10 of 28 cell-compound pairs showing significant shifts in growth-inhibitory activity. Varying mir-21 levels changed potencies in opposite directions depending on compound class; indicating that different mechanisms determine toxic and protective effects. In silico comparison of drug potencies with microRNA expression profiles across the entire NCI-60 panel revealed that approximately 30 microRNAs, including mir-21, show highly significant correlations with numerous anticancer agents. Ten of those microRNAs have already been implicated in cancer biology. Our results support a substantial role for microRNAs in anticancer drug response, suggesting novel potential approaches to the improvement of chemotherapy.
Highlights
The molecular genetic basis of sensitivity and resistance to cancer therapeutics is complex, involving multiple processes such as drug transport, drug metabolism, DNA repair, and apoptosis
Because of the ease of detection on a large scale, expression profiling has been most extensive at the mRNA level, but levels of mRNA and the encoded proteins are often not proportional
Because many of the same biological processes are relevant to cancer chemosensitivity and chemoresistance, we hypothesized that microRNAs could broadly affect the response to anticancer drugs
Summary
The molecular genetic basis of sensitivity and resistance to cancer therapeutics is complex, involving multiple processes such as drug transport, drug metabolism, DNA repair, and apoptosis. To follow up on those pilot findings, we selected three microRNAs previously implicated in cancer, mir-21, let-7i, and mir-16, and tested the effect of their expression on the potencies of a number of compounds with anticancer activity.
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