Let‐7 modulates acquired resistance of ovarian cancer to Taxanes via IMP‐1‐mediated stabilization of multidrug resistance 1

Abstract

Ovarian cancer patients frequently develop resistance to chemotherapy regiments using Taxol and carboplatin. One of the resistance factors that protects cancer cells from Taxol‐based therapy is multidrug resistance 1 (MDR1). micro(mi)RNAs are small noncoding RNAs that negatively regulate protein expression. Members of the let‐7 family of miRNAs are downregulated in many human cancers, and low let‐7 expression has been correlated with resistance to microtubule targeting drugs (Taxanes), although little is known that would explain this activity. We now provide evidence that, although let‐7 is not a universal sensitizer of cancer cells to Taxanes, it affects acquired resistance of cells to this class of drugs by targeting IMP‐1, resulting in destabilization of the mRNA of MDR1. Introducing let‐7g into ADR‐RES cells expressing both IMP‐1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin, a non‐MDR1 substrate. This effect could be reversed by reintroducing IMP‐1 into let‐7g high/MDR1 low cells causing MDR1 to again become stabilized. Consistently, many relapsed ovarian cancer patients tested before and after chemotherapy were found to downregulate let‐7 and to co‐upregulate IMP‐1 and MDR1, and the increase in the expression levels of both proteins after chemotherapy negatively correlated with disease‐free time before recurrence. Our data point at IMP‐1 and MDR1 as indicators for response to therapy, and at IMP‐1 as a novel therapeutic target for overcoming multidrug resistance of ovarian cancer.