Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis

Abstract

Chronic stress is associated with hormonal changes that are known to affect multiple systems, including the immune and endocrine systems, but the effects of stress on cancer growth and progression are not fully understood. Here, we demonstrate that human ovarian cancer cells exposed to either norepinephrine or epinephrine exhibit lower levels of anoikis, the process by which cells enter apoptosis when separated from ECM and neighboring cells. In an orthotopic mouse model of human ovarian cancer, restraint stress and the associated increases in norepinephrine and epinephrine protected the tumor cells from anoikis and promoted their growth by activating focal adhesion kinase (FAK). These effects involved phosphorylation of FAK Y397 , which was itself associated with actin-dependent Src interaction with membrane-associated FAK. Importantly, in human ovarian cancer patients, behavioral states related to greater adrenergic activity were associated with higher levels of pFAK Y397 , which was in turn linked to substantially accelerated mortality. These data suggest that FAK modulation by stress hormones, especially norepinephrine and epinephrine, can contribute to tumor progression in patients with ovarian cancer and may point to potential new therapeutic targets for cancer management.

Chronic stress, sympathetic activation and skeletal metastasis of breast cancer cells

“…This could affect early metastatic events such as tumor cell invasion, angiogenesis of the primary tumor, cancer cell survival or resistance to chemotherapy, as shown in studies related to other types of solid cancers. 42,43,[69][70][71][72][73][74][75] A stromal-mediated mechanism also implies that other types of metastatic cancers may be influenced by depression, chronic stress and subsequent sympathetic activation. 42,[70][71][72]75 The relative contribution of activation of the HPA axis and adrenal-derived epinephrine (versus nerve-derived NE) to bone remodeling and metastasis remains to be better characterized.…”

“…Sood et al also reported that chronic stress induced by daily restrain or ISO injections protected tumor cells from apoptosis upon loss of anchorage and detachment of the extracellular matrix in an orthotopic model of human ovarian cancer. 43 Other studies indicated that bAR stimulation increases the expression of VEGF and angiogenesis in human breast ovarian and melanoma cancer cells 42,44,45 and pro-metastatic matrix metalloproteinases and other inflammatory mediators in gastric tumors. 46 aAR blockade was also shown to block the proliferative effect of catecholamines on breast cancer cells in vitro, 47 although the stimulatory effect of catecholamine on breast cancer cells is not seen in all studies.…”

A Review of Cancer Immunotherapy and Nutritional Therapies

“…Stress also can indirectly promote cancer by weakening the immune system through releasing high levels of cortisol and epinephrine. Many studies have shown that these hormones make breast, ovarian and prostate cancer cells resistant to destruction [24][25][26].…”

Cancer Interception

“…A recent study of psychosocial factors has shown that psychological stress increases cancer progression in the breast and ovaries, but it is unclear if it also increases cancer risk (43). A study of the influence of psychosocial stress on molecular changes in metastasis identified molecular targets that could lead to the interception of metastasis development; for example, such a target was suggested by recent work showing the mechanistic link between adrenergic stress and focal adhesion kinase (FAK) activation (which protects cells from anoikis), supporting the potential of b-2 adrenergic receptor blockers to intercept metastasis (44). Although clinical therapy trials in advanced cancers are only just beginning to target telomerase activity, there are many other genes involved in regulation of telomere function and many cellular pathways that can indirectly affect it (e.g., DNA repair pathways).…”