Survival Mechanisms of Metastatic Melanoma Cells: The Link between Glucocorticoids and the Nrf2-Dependent Antioxidant Defense System.
Elena ObradorRosario Salvador PalmerRafael López-BlanchMaría Oriol-CaballoPaz Moreno-MurcianoJosé M EstrelaPublished in: Cells (2023)
Circulating glucocorticoids increase during stress. Chronic stress, characterized by a sustained increase in serum levels of cortisol, has been associated in different cases with an increased risk of cancer and a worse prognosis. Glucocorticoids can promote gluconeogenesis, mobilization of amino acids, fat breakdown, and impair the body's immune response. Therefore, conditions that may favor cancer growth and the acquisition of radio- and chemo-resistance. We found that glucocorticoid receptor knockdown diminishes the antioxidant protection of murine B16-F10 (highly metastatic) melanoma cells, thus leading to a drastic decrease in their survival during interaction with the vascular endothelium. The BRAF V600E mutation is the most commonly observed in melanoma patients. Recent studies revealed that VMF/PLX40-32 (vemurafenib, a selective inhibitor of mutant BRAF V600E ) increases mitochondrial respiration and reactive oxygen species (ROS) production in BRAF V600E human melanoma cell lines. Early-stage cancer cells lacking Nrf2 generate high ROS levels and exhibit a senescence-like growth arrest. Thus, it is likely that a glucocorticoid receptor antagonist (RU486) could increase the efficacy of BRAF-related therapy in BRAF V600E -mutated melanoma. In fact, during early progression of skin melanoma metastases, RU486 and VMF induced metastases regression. However, treatment at an advanced stage of growth found resistance to RU486 and VMF. This resistance was mechanistically linked to overexpression of proteins of the Bcl-2 family (Bcl-xL and Mcl-1 in different human models). Moreover, melanoma resistance was decreased if AKT and NF-κB signaling pathways were blocked. These findings highlight mechanisms by which metastatic melanoma cells adapt to survive and could help in the development of most effective therapeutic strategies.
Keyphrases
- oxidative stress
- wild type
- reactive oxygen species
- endothelial cells
- signaling pathway
- metastatic colorectal cancer
- early stage
- skin cancer
- immune response
- induced apoptosis
- dna damage
- squamous cell carcinoma
- small cell lung cancer
- cell death
- diabetic rats
- papillary thyroid
- end stage renal disease
- cell proliferation
- high glucose
- squamous cell
- ejection fraction
- nitric oxide
- pi k akt
- basal cell carcinoma
- photodynamic therapy
- adipose tissue
- chronic kidney disease
- amino acid
- induced pluripotent stem cells
- stress induced
- energy transfer
- cell cycle arrest
- radiation therapy
- stem cells
- drug induced
- toll like receptor
- lps induced
- dendritic cells
- mesenchymal stem cells
- transcription factor
- epithelial mesenchymal transition
- free survival
- lymph node metastasis
- prognostic factors
- lymph node
- replacement therapy
- sentinel lymph node