A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel

Liqin Du, Robert Borkowski, Zhenze Zhao, Xiuye Ma, Xiaojie Yu, Xian Jin Xie, Alexander Pertsemlidis

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1700-1713
Number of pages14
JournalRNA Biology
Volume10
Issue number11
DOIs
StatePublished - Nov 2013

Fingerprint

Paclitaxel
MicroRNAs
Lung Neoplasms
Cell Survival
Caspase 7
Cell Cycle Checkpoints
S Phase
Caspase 3
Libraries
Therapeutics
RNA

Keywords

  • Cell viability
  • Drug response
  • Lung cancer
  • miRNA
  • Paclitaxel

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Du, L., Borkowski, R., Zhao, Z., Ma, X., Yu, X., Xie, X. J., & Pertsemlidis, A. (2013). A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel. RNA Biology, 10(11), 1700-1713. https://doi.org/10.4161/rna.26541

A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel. / Du, Liqin; Borkowski, Robert; Zhao, Zhenze; Ma, Xiuye; Yu, Xiaojie; Xie, Xian Jin; Pertsemlidis, Alexander.

In: RNA Biology, Vol. 10, No. 11, 11.2013, p. 1700-1713.

Research output: Contribution to journalArticle

Du, L, Borkowski, R, Zhao, Z, Ma, X, Yu, X, Xie, XJ & Pertsemlidis, A 2013, 'A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel', RNA Biology, vol. 10, no. 11, pp. 1700-1713. https://doi.org/10.4161/rna.26541
Du, Liqin ; Borkowski, Robert ; Zhao, Zhenze ; Ma, Xiuye ; Yu, Xiaojie ; Xie, Xian Jin ; Pertsemlidis, Alexander. / A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel. In: RNA Biology. 2013 ; Vol. 10, No. 11. pp. 1700-1713.
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