Stress and drug resistance in cancer

Abstract

Patients diagnosed with cancer often undergo considerable psychological distress, and the induction of the psychological stress response has been linked with a poor response to chemotherapy. The psychological stress response is mediated by fluctuations of the hormones glucocorticoids (GCs) and catecholamines. Binding to their respective receptors, GCs and the catecholamines adrenaline/noradrenaline are responsible for signalling a wide range of processes involved in cell survival, cell cycle and immune function. Synthetic GCs are also often prescribed as co-medication alongside chemotherapy, and increasing evidence suggests that GCs may induce chemoresistance in multiple cancer types. In this review, we bring together evidence linking psychological stress hormone signalling with resistance to chemo- and immune therapies, as well as mechanistic evidence regarding the effects of exogenous stress hormones on the efficacy of chemotherapies.

Keywords: Cancer; catecholamines; dexamethasone; drug resistance; glucocorticoids.

Figure 1

Stress hormone mechanism of action. The HPA signals the release of glucocorticoids. Activation of the GR mediates transactivation and transrepression of genes through binding to the GRE, which controls the expression of genes involved in inflammation, survival and apoptosis. Stimulation of the SNS promotes the release of catecholamines. Activation of the BADR by adrenaline/noradrenaline stimulates synthesis of cAMP which in turn activates PKA. Phosphorylation of a number of PKA-receptive proteins involved in cell survival, proliferation and gene transcription can then occur. HPA: hypothalamic-pituitary-axis; GR: glucocorticoid receptor; GRE: glucocorticoid response element; SNS: sympathetic nervous system; BADR: beta-adrenergic receptor; cAMP: cyclic adenosine monophosphate; PKA: protein kinase A

Figure 2

DNA damage response. DNA damage induced by stress hormones activates the DNA damage sensors ATM and ATR, which initiate downstream signal cascades controlling DNA repair, cell cycle arrest and apoptosis. ATM: ataxia-telangiectasia mutated; ATR: ataxia telangiectasia and Rad3-related

Figure 3

Glucocorticoids and chemoresistance. Glucocorticoids can reduce the efficacy of chemotherapeutics (taxanes and platinum-based drugs) through upregulation of cell survival signalling, downregulation of apoptosis and interference with DNA repair mechanisms

Figure 4

Stress hormone-mediated immune regulation. Glucocorticoids immune regulation is associated with the blockade of the pro-inflammatory gene expression. GCs bind the cytoplasmic glucocorticoid receptors (GRs) and translocate to the nucleus where they inhibit transcriptional factors such as NF-κB or AP-1 that regulate the expression of pro-inflammatory genes. Catecholamines can bind G-protein coupled adrenergic receptors on the membrane of immune T cells. The adrenergic signalling pathway blocks the production of the pro-inflammatory cytokine IFN-γ and consequently B cell production of IgG2a. On the contrary, β-adrenergic signalling is not thought to affect Th2 cells producing of IL-4 or B cells producing IgG1. Both GCs and the adrenergic hormones affect the T cell migration by regulating the T cell cytoskeleton and actin-binding proteins such as moesin. This leads to the hypothesis that stress hormones can have a role in the T cell trafficking into the tumour. Furthermore, stress hormones exposure correlates with the loss of the activation immune marker CD43.GCs: glucocorticoids; GRs: glucocorticoid receptors