Glucocorticoid inhibits lung cancer cells proliferation and migration by suppressing smad2/3 activation

Glucocorticoid (GCs), as an adjuvant drug, is widely used for alleviating chemotherapy or immunotherapy-induced adverse events, such as nausea and immune-related diseases in lung cancer treatment. However, whether GCs directly affects lung cancer progression remains unclear. This study focused on the effects of dexamethasone (DEX) on the proliferation and migration of lung cancer cells as well as the related potential mechanisms using EdU, CCK8, Transwell, Wound healing, TCGA database, HPA database, qPCR and Western blotting. Additionally, subcutaneous tumor and tail vein tumor injection models were established for investigating DEX action in vivo. Further, to confirm the key functional of Smad2/3 for DEX regulating lung cancer cells proliferation and migration. Mechanistic assays explored the upstream regulatory molecules TGFβ1, TGFβR1 and p-TGFβR1 expression after DEX treatment. Moreover, DEX modulates lung cancer cell proliferation and migration on a glucocorticoid receptor (GR)-independent manner and the association with Smad2/3 activation were investigated. Results: The results showed that DEX (1 µM) treatment significantly inhibited the proliferation and the migration of lung cancer cells A549 and LLC cells. TCGA and HPA databases showed Smad2/3 expression was positively correlated with lung cancer progression. Mechanistically, DEX treatment significantly inhibited Smad2/3 activation in vitro and in vivo, manifested as a decrease in the expression of p-Smad2 (Ser465/467), Smad2, p-Smad3 (Ser423/425), and Smad3. Smad2/3 knockdown significantly inhibit the proliferation, migration and Smad2/3 activity of A549 and LLC cells. Creatine, the agonist of Smad2/3 activation, markedly reversed the inhibitory effects of DEX on the proliferation and migration of A549 and LLC cells. Smad2/3 overexpression also reversed the inhibitory effects of DEX on A549 cell proliferation and migration. Further studies showed DEX inhibited the expression of TGFβR1 and p-TGFβR1(Ser165) and the levels of TGFβ1. Moreover, GR knockout significantly promoted the proliferation, migration and Smad2/3 activity in A549 cell. DEX can inhibits A549 cell proliferation and migration through suppressing Smad2/3 activation independent of GR. Conclusion: DEX inhibited the proliferation and migration of lung cancer cells by suppressing Smad2/3 activation, providing a theoretical basis and experimental data for clinical practice.