Abstract 4224: MiR-7 and its novel target regulate sensitivity to microtubule stabilizing agents

Abstract

Abstract Microtubule stabilizing drugs, such as Taxol that is used in the treatment of numerous malignancies, cause distinct responses in cancer cells, including apoptosis, mitotic catastrophe, necrosis and accelerated senescence. However, drug resistance, a complex and mutlifactorial phenotype, is a major obstacle to therapy and the foremost cause of disease progression and cancer-related mortality. MiRNAs are small non-coding RNAs that regulate protein expression by targeting their 3′UTRs, and are emerging as key regulators of cancer pathogenesis that can influence sensitivity to chemotherapy and radiotherapy. We have identified miR-7 as a regulator of sensitivity to the microtubule-stabilizing agents, discodermolide and Taxol. Over-expression of miR-7 in the lung cancer cell lines A549 and H2122, strongly inhibited cell proliferation and sensitized the cells to drug-induced apoptosis. Over-expression of miR-7 also increased the number of acidic lysosomes, as measured by β-galactosidase activity, which likely reflects lysosomal stress. It also increased basal and drug-induced caspase activation, which most likely mediate the sensitizing effects of discodermolide and Taxol. In addition, we validated that the transcription factor, Kruppel like factor 4 (KLF4) is a target of miR-7, and that its expression also regulates sensitivity to discodermolide and Taxol. KLF4 is suppressed in discodermolide- and Taxol-treated A549 cells that have a strong senescent phenotype, and is over-expressed in A549 cells that are resistant to either drugs. ShRNA-mediated knockdown of KLF4 in A549 and H2122 also sensitized cells to discodermolide and Taxol though to a lesser degree than miR-7 overexpression, and also inhibited cell proliferation and increased lysosomal β-galactosidase activity and caspase activity. Thus, we hypothesize that suppression of KLF4 partially mediates the potent anti-tumor effects of miR-7 in A549 and H2122 lung cancer cells. In summary, we have identified miR-7 and its novel target, KLF4, as important regulators of sensitivity to discodermolide and Taxol, and suggest that miR-7 is a promising candidate for therapeutic development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4224. doi:1538-7445.AM2012-4224