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

Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
The Journal of clinical investigation (Impact Factor: 13.77). 04/2010; 120(5):1515-23. DOI: 10.1172/JCI40802
Source: PubMed

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 FAKY397, 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 pFAKY397, 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.

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Available from: Pablo E Vivas-Mejia, Aug 23, 2015
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    • "Many studies have shown that chronic stress can increase tumor development and/or disease progression (e.g., metastsis of solid tumors or dissemination of hematopoietic tumors). Pharmacologic and molecular dissection of these models has identified a diverse array of gene modules that appear to play a role in mediating such effects, including glucocorticoid-induced activation of the SGK1 gene and associated inhibition of the key tumor suppressor p53 (Feng et al., 2012), and b-adrenergic induction of genes involved in macrophage recruitment and inflammation (Sloan et al., 2010), induction of pro-inflammatory cytokine genes such as IL6 and IL8 by tumor cells (Cole et al., 2010; Nilsson et al., 2007; Shahzad et al., 2010) and immune cells (Cole et al., 2010), VEGF-mediated increases in angiogenesis (Chakroborty et al., 2009; Thaker et al., 2006; Yang et al., 2006), matrix metalloproteinase-related increases in tissue invasion (Landen et al., 2007; Sood et al., 2006; Yang et al., 2006), tumor cell mobilization and motility (Drell et al., 2003; Lang et al., 2004; Palm et al., 2006), FAKmediated resistance to anoikis/apoptosis (Sood et al., 2010), BADmediated resistance to chemotherapy-induced apoptosis (Sastry et al., 2007), and RANKL-mediated modulation of osteoclast function and bone metastasis (Campbell et al., 2012). Other studies have also shown that glucocorticoids can up-regulate a diverse array of genes involved in cell survival and resistance to chemotherapy (Kamradt et al., 2000a; Mikosz et al., 2001; Moran et al., 2000; Pang et al., 2006; Petrella et al., 2006; Wu et al., 2004, 2005), and activate oncogenic viruses such as Epstein–Barr Virus (EBV) (Cacioppo et al., 2002; Glaser et al., 1995; Yang et al., 2010) and Human Papilloma Viruses (Kamradt et al., 2000b; Mittal et al., 1993; Pater et al., 1988), and that b-adrenergic signaling can inhibit p53-med- iated DNA repair (Hara et al., 2011), inhibit expression of Type I interferons (Collado-Hidalgo et al., 2006; Sloan et al., 2010) and interleukin 12 (Goldfarb et al., 2011), upregulate the Her2 signaling pathway implicated in breast cancer (Gu et al., 2009; Shi et al., 2011), stimulate arachadonic acid signaling (Cakir et al., 2002), activate gene expression by tumor-promoting viruses such as HHV-8 (Antoni et al., 2006; Chang et al., 2005), and upregulate the SNAI2 transcription factor regulating epithelial–mesenchymal transition (S. "
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