Survival Mechanisms of Metastatic Melanoma Cells: The Link between Glucocorticoids and the Nrf2-Dependent Antioxidant Defense System

Abstract

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 BRAFV600E mutation is the most commonly observed in melanoma patients. Recent studies revealed that VMF/PLX40-32 (vemurafenib, a selective inhibitor of mutant BRAFV600E) increases mitochondrial respiration and reactive oxygen species (ROS) production in BRAFV600E 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 BRAFV600E-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.

Effect of comfort nursing in the perioperative period of free flap transplantation to repair the defects after surgery for malignant head and neck tumors

“…During stress, an increase in glucocorticoid levels has extensive protective effects on the body but also has adverse effects on patients. [ 21 ] First of all, the increase in glucocorticoids is an important mechanism for the increase in blood glucose during stress. It promotes the decomposition of fat and peripheral tissue proteins, generates a large number of free amino acids and fatty acids, and promotes gluconeogenesis and glucagon mobilization.…”

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

“…This has implications as to how the CAR and the stress-associated hypothalamus-pituitary-adrenal (HPA) axis activation can modulate the immune response and highlights the attenuation of GR effects by melatonin. The priming effect of pineal melatonin on GR translocation and effects has significant implications for the physiological consequences of CAR and during stress activation of the HPA axis [ 42 ], and therefore in how CAR and stress driven HPA axis activation associate with cancer pathogenesis [ 45 ], progression [ 46 ] and treatment [ 47 ]. This would indicate that pineal melatonin suppression over aging, as well as by inflammation [ 48 ], lipopolysaccharide (LPS) [ 49 ] and miRNAs [ 50 ] will have significant consequences for how CAR prepares systemic cells, including patterned immune responses, for the coming day.…”

“…A plethora of data show melatonin [58,59], including indirectly [60,61] to modulate all immune cells, although seldom are the interactions of melatonin and GR activation investigated in immune cells. In studies investigating GR and melatonin interactions, it is clear that melatonin significantly modulates GR effects, including via FKBP4 regulation [62], as shown in immune cells [45]. It is widely recognized that glucocorticoid treatments, by suppressing NK cells and cytolytic cells, enhances cancer pathogenesis [61], thereby linking to how stress induced HPA axis activation and glucocorticoid treatment increase cancer susceptibility and modulate progression [63].…”

Reactive Oxygen Species: A Crosslink between Plant and Human Eukaryotic Cell Systems

“…For example, the activation of splenic nerves can improve B cell responses and antibody production in response to protein immunization [171]. Hormones are transported through the bloodstream to regulate systemic effects, such as an increase in circulating glucocorticoids during stress, which can promote gluconeogenesis, mobilize amino acids, break down fats, and impair the body's immune response [172]. This also results in a relatively lower tolerance to reactive oxygen species (ROS) in the human body, making them more sensitive to changes in ROS levels.…”