1. Dexamethasone induces cancer mitigation and irreversible senescence in lung cancer cells via damaging cortical actin and sustained hyperphosphorylation of pRb.
- Author
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Srivastava S, Siddiqui S, Singh S, Chowdhury S, Upadhyay V, Sethi A, and Kumar Trivedi A
- Subjects
- Humans, Retinoblastoma Protein metabolism, Actins, Dexamethasone pharmacology, Dexamethasone therapeutic use, Receptors, Glucocorticoid metabolism, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Carcinoma, Non-Small-Cell Lung metabolism
- Abstract
Activation of the glucocorticoid receptors by its cognate ligand, dexamethasone (DEX) is commonly used as an adjuvant treatment in solid tumors. However, its direct effect on cancerous phenotype is not fully understood. We explored the effect and molecular mechanisms of DEX action in lung cancer. In in vitro experiments, DEX treatment causes decrease in migration, invasion and colony formation ability of A549 cells even at lower doses. DEX also decreased adhesion of A549 cells by reducing the formation of cortical actin. Treatment with RU486, a GR antagonist, indicated that these effects are partially mediated through GR. Further; DEX induces G0/G1 arrest of A549 cells. Mechanistically, DEX induces expression of both CDK inhibitors (p21
Cip1 , p27Kip1 ) and cyclin-dependent kinases (CDK4, CDK6). Due to this compensatory activation of CDKs and CDKIs, DEX induces the hyper phosphorylation state of Rb protein (pRb) leading to irreversible senescence as confirmed by β-gal staining. Next, in clinical dataset of NSCLC (Non-small cell lung cancer), GR was lowly expressed in cancer patients as compared to the normal group, where higher expression of GR led to higher overall survival of NSCLC indicating for a protective role of GR. Interestingly, when combined with chemotherapeutic agents, DEX can modulate the drug-sensitivity of cells. Taken together, these data indicate that DEX through GR activation may suppress tumor growth by decreasing proliferation and inducing irreversible senescence and combination of standard chemotherapy and DEX can be a potential treatment for NSCLC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
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