microRNAs: a role in drug resistance in parasitic nematodes?

Abstract

Drug resistance in parasitic nematodes is an increasing problem worldwide, with resistance reported to all three commonly used classes of anthelmintics. Most studies to date have sought to correlate the resistant phenotype with genotypic changes in putative target molecules. Although this approach has identified mutations in several relevant genes, resistance might result from a complex interaction of different factors. Here we propose an alternative mechanism underlying the development of drug resistance based on functional differences in microRNA activity in resistant parasites. microRNAs play an important role in resistance to chemotherapeutic agents in many tumour cells and here we discuss whether they might also be involved in anthelmintic resistance in parasitic nematodes.

Figure 1

Potential mechanisms for miRNA involvement in drug resistance. (a) In human MCF-7 breast cancer cells, miR-451 negatively regulates translation of the P-glycoprotein gene mdr-1, via a complementary miR-451 site in the 3′-UTR of mdr-1. In MCF-7 cells resistant to doxorubicin (MCF-7/DOX), decreased levels of miR-451 result in an increased level of MDR-1 protein with resultant DOX resistance . (b) In C. elegans, miR-1 negatively regulates the unc-29 nAChR subunit via three complementary sites in the unc-29 3′UTR. In mir-1 null mutants, UNC-29 protein level is increased, which alters nAChR composition, leading to a decreased sensitivity to levamisole .

Figure I