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.
Highlights
This TTF-1-dependent, heightened cisplatin sensitivity did not extend to another platinum chemotherapy – carboplatin (Fig. S2A,B); nor could we detect a TTF-1-dependent differential sensitivity toward gemcitabine (Fig. S2C,D), a chemotherapy sometimes used in combination with cisplatin for advanced nonsmall cell lung cancer (NSCLC)[26]
We surmised that the impact of TTF-1 on cellular cisplatin sensitivity may be connected to NER in view of the report that TTF-1 interacts with Damaged DNA binding protein 1 (DDB1)[5]
The known interaction between TTF-1 and DDB1 may compromise the NER-directed repair of cisplatin-induced DNA damages, which would presumably lead to a heightened sensitivity to cisplatin
Summary
IC50 calculations implicated a significant increase (>80%) in cisplatin sensitivity of A549-TTF-1 cells (6.14 μM ± 0.78 μM SEM) in comparison with the EV control (11.28 μM ± 1.47 μM SEM, Fig. 1B). The TTF-1 transfectant cells were more sensitive to cisplatin than the EV and HDD control cells (Fig. S1A,B). In a human lung cancer cell line that does not harbor either KRAS or EGFR mutations, i.e. NCI-H1437 (TP53R267P), intriguingly, TTF-1 did not significantly alter its cisplatin sensitivity (Fig. S4C,D).
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