title: A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel.
abstract: microRNAs (miRNAs) are small RNAs endogenously expressed in multiple organisms that regulate gene expression largely by decreasing levels of target messenger RNAs (mRNAs). Over the past few years, numerous studies have demonstrated critical roles for miRNAs in the pathogenesis of many cancers, including lung cancer. Cellular miRNA levels can be easily manipulated, showing the promise of developing miRNA-targeted oligos as next-generation therapeutic agents. In a comprehensive effort to identify novel miRNA-based therapeutic agents for lung cancer treatment, we combined a high-throughput screening platform with a library of chemically synthesized miRNA inhibitors to systematically identify miRNA inhibitors that reduce lung cancer cell survival and those that sensitize cells to paclitaxel. By screening three lung cancer cell lines with different genetic backgrounds, we identified miRNA inhibitors that potentially have a universal cytotoxic effect on lung cancer cells and miRNA inhibitors that sensitize cells to paclitaxel treatment, suggesting the potential of developing these miRNA inhibitors as therapeutic agents for lung cancer. We then focused on characterizing the inhibitors of three miRNAs (miR-133a/b, miR-361-3p, and miR-346) that have the most potent effect on cell survival. We demonstrated that two of the miRNA inhibitors (miR-133a/b and miR-361-3p) decrease cell survival by activating caspase-3/7-dependent apoptotic pathways and inducing cell cycle arrest in S phase. Future studies are certainly needed to define the mechanisms by which the identified miRNA inhibitors regulate cell survival and drug response, and to explore the potential of translating the current findings into clinical applications.
authors.affiliation: Greehey Children's Cancer Research Institute; Department of Cellular and Structural Biology; UT Health Science Center at San Antonio; San Antonio, TX USA.
authors.forename: Liqin
authors.initials: L
authors.lastname: Du
authors.affiliation: Division of Basic Sciences; Southwestern Graduate School of Biomedical Sciences; UT Southwestern Medical Center; Dallas, TX USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Borkowski
authors.affiliation: Greehey Children's Cancer Research Institute; Department of Cellular and Structural Biology; UT Health Science Center at San Antonio; San Antonio, TX USA.
authors.forename: Zhenze
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Greehey Children's Cancer Research Institute; Department of Cellular and Structural Biology; UT Health Science Center at San Antonio; San Antonio, TX USA.
authors.forename: Xiuye
authors.initials: X
authors.lastname: Ma
authors.affiliation: Graduate School of Biomedical Sciences; UT Health Science Center at San Antonio; San Antonio, TX USA.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Clinical Sciences; UT Southwestern Medical Center; Dallas, TX USA.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Greehey Children's Cancer Research Institute; Department of Cellular and Structural Biology; UT Health Science Center at San Antonio; San Antonio, TX USA; Greehey Children's Cancer Research Institute; Department of Pediatrics; UT Health Science Center at San Antonio; San Antonio, TX USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pertsemlidis
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D053470:Caspases, Effector / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D057166:High-Throughput Screening Assays; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D017239:Paclitaxel / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C548234:MIRN133 microRNA, human; C560923:MIRN346 microRNA, human; C575475:MIRN361 microRNA, human; D035683:MicroRNAs; D053470:Caspases, Effector; D017239:Paclitaxel
keywords: cell viability; drug response; lung cancer; miRNA; paclitaxel