p38 MAPK-dependent Rapid Activation of Glucocorticoid Receptors
Platinum-based chemotherapy is commonly used for treating hematological malignancies and solid tumors, including breast and ovarian cancers. To mitigate the adverse effects of these therapies, corticosteroids (e.g., dexamethasone) are often co-administered. However, these agents can compromise the efficacy of chemotherapy. Glucocorticoid receptors (GR) function as ligand-activated transcription factors that promote cancer cell survival and contribute to metastasis. Similarly, Transforming Growth Factor Beta 1 (TGFB1) has comparable effects on tumor survival and metastasis. In triple negative breast cancer (TNBC), in the absence of GR ligands, TGFB1 activates the p38-dependent phosphorylation of GR on Ser134 (p-GR). This event induces the transcriptional regulation of p-GR-dependent genes crucial for cell survival and migration. This study aimed to investigate the ligand-independent actions of p-GR in OC. Western blot analysis demonstrated rapid phosphorylation of GR on Ser134 in OVCAR-8 and PEO4 cells upon treatment with either TGFB1 or dexamethasone; GR Ser134 phosphorylation was blocked with the p38 inhibitor, SB202190. Additionally, TGF!1 or dexamethasone induced the upregulation of pro-survival genes and increased soft agar colony formation, suggesting that OC cells, like TNBC cells, employ p-GR-driven mechanisms to promote advanced cancer phenotypes. Future directions will examine the mechanisms of gene regulation by p-GR in additional OC models.