Cisplatin sensitivity mediated by WEE1 and CHK1 is mediated by miR-155 and the miR-15 family.

Paradigms and Technologies
Methods Development

Abstract

Resistance to platinum-based therapies arises by multiple mechanisms, including by alterations to cell-cycle kinases that mediate G(2)-M phase arrest. In this study, we conducted parallel high-throughput screens for microRNAs (miRNA) that could restore sensitivity to cisplatin-resistant cells, and we screened for kinases targeted by miRNAs that mediated cisplatin resistance. Overexpression of the cell-cycle kinases WEE1 and CHK1 occurred commonly in cisplatin-resistant cells. miRNAs in the miR-15/16/195/424/497 family were found to sensitize cisplatin-resistant cells to apoptosis by targeting WEE1 and CHK1. Loss-of-function and gain-of-function studies showed that miR-15 family members controlled the expression of WEE1 and CHK1. Supporting these results, we found that in the presence of cisplatin altering expression of miR-16 or related genes altered cell cycle distribution. Our findings reveal critical regulation of miRNAs and their cell-cycle-associated kinase targets in mediating resistance to cisplatin.

Authors

Pouliot, Lynn M; Chen, Yu-Chi; Bai, Jennifer; Guha, Rajarshi; Martin, Scott E; Gottesman, Michael M; Hall, Matthew;

Keywords

  • Antineoplastic Agents/ pharmacology
  • Ataxia Telangiectasia Mutated Proteins
  • Carcinoma, Squamous Cell/ drug therapy
  • Carcinoma, Squamous Cell/ enzymology
  • Carcinoma, Squamous Cell/ genetics
  • Cell Cycle Proteins/ antagonists & inhibitors
  • Cell Cycle Proteins/ biosynthesis
  • Cell Cycle Proteins/ genetics
  • Cell Line, Tumor
  • Cisplatin/ pharmacology
  • Drug Resistance, Neoplasm
  • High-Throughput Screening Assays
  • Humans
  • MicroRNAs/ antagonists & inhibitors
  • MicroRNAs/ genetics
  • Nuclear Proteins/ antagonists & inhibitors
  • Nuclear Proteins/ biosynthesis
  • Nuclear Proteins/ genetics
  • Protein Kinase Inhibitors/ pharmacology
  • Protein Kinases/ biosynthesis
  • Protein Kinases/ genetics
  • Protein-Serine-Threonine Kinases/ biosynthesis
  • Protein-Serine-Threonine Kinases/ genetics
  • Protein-Tyrosine Kinases/ antagonists & inhibitors
  • Protein-Tyrosine Kinases/ biosynthesis
  • Protein-Tyrosine Kinases/ genetics
  • RNA Interference
  • RNA, Small Interfering/ administration & dosage
  • RNA, Small Interfering/ genetics
  • Transfection

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