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Publication Detail

Title: Mechanistic Study of TTF-1 Modulation of Cellular Sensitivity to Cisplatin.

Authors: Phelps, Cody A; Lindsey-Boltz, Laura; Sancar, Aziz; Mu, David

Published In Sci Rep, (2019 05 29)

Abstract: 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.

PubMed ID: 31142791 Exiting the NIEHS site

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

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