Mechanistic Study of TTF-1 Modulation of Cellular Sensitivity to Cisplatin

Sci Rep. 2019 May 29;9(1):7990. doi: 10.1038/s41598-019-44549-w.


The lung lineage master regulator gene, Thyroid Transcription Factor-1 (TTF-1, also known as NKX2-1), is used as a marker by pathologists to identify lung adenocarcinomas since TTF-1 is expressed in 60 ~ 70% of lung ADs. Much research has been conducted to investigate roles of TTF-1 in lung cancer biology. But, how it modulates cellular chemosensitivity remains poorly characterized. Our study shows that TTF-1 sensitizes the KRAS-mutated A549 and NCI-H460 lung cancer cells to cisplatin, a common chemotherapy used to treat lung cancer. This chemosensitization activity does not appear to be mediated by a TTF-1-imposed alteration on nucleotide excision repair. Mechanistically, TTF-1 induced a reduction in p-AKT (S473), which in turn activated glycogen synthase kinase 3 (GSK3) and reduced β-catenin. Intriguingly, in the EGFR-mutated NCI-H1975 and HCC827 cells, TTF-1 desensitized these cells to cisplatin; concomitantly, TTF-1 conferred an increase in p-AKT. Finally, the conditioned media of TTF-1-transefected cells sensitized TTF-1- cells to cisplatin, implicating that the TTF-1-driven chemosensitization activity may be dually pronged in both intracellular and extracellular compartments. In short, this study highlights the enigmatic activities of TTF-1 in lung cancer, and calls for future research to optimally manage chemotherapy of patients with TTF-1+ lung ADs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adenocarcinoma of Lung / drug therapy*
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / pathology
  • Biomarkers, Tumor / genetics
  • Cell Lineage / genetics*
  • Cisplatin / adverse effects
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm / drug effects
  • ErbB Receptors / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycogen Synthase Kinase 3 / genetics
  • Humans
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Thyroid Nuclear Factor 1 / genetics*
  • beta Catenin / genetics


  • Biomarkers, Tumor
  • CTNNB1 protein, human
  • KRAS protein, human
  • Thyroid Nuclear Factor 1
  • beta Catenin
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Proto-Oncogene Proteins p21(ras)
  • Cisplatin