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: 13.22). 04/2010; 120(5):1515-23. DOI: 10.1172/JCI40802
Source: PubMed


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
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    • "Also, increases in NE in organs that are typical metastatic sites for ovarian cancer have been reported [2]. Sook et al found that the intratumoral catecholamine differences observed affect biological pathways involved in tumor progression such as angiogenesis, invasion, anoikis, transcription pathway activation, etc [18]. Others have shown a possible link between psychosocial distress and increased risk of metastasis [2]. "
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    ABSTRACT: Background Noradrenergic pathways and glucocorticoid-mediated signal pathways have been implicated in the growth and progression of oral cancer. Patients with oral neoplasms can have high psychological distress levels, but the effects of stress-related hormones on oral neoplasm growth are unknown. Methods We have investigated the relationships between pre-surgical measurements of psychological problems with Symptom Checklist-90-revised Inventory (SCL90-R), tumor histology, circulating blood catecholamine and glucocorticoid levels among 75 oral neoplasm patients, including 40 oral cancer patients and 35 benign oral tumor patients. Results The results showed that most dimension scores of SCL90-R did not show a significant difference between the two groups except depression (p = 0.0201) and obsessive-compulsion (p = 0.0093), with the scores for these symptoms being higher among oral cancer group versus the benign oral tumor group. The differences of total score, average score and other monomial factor scores were not statistically significant. The mean concentrations of catecholamine and glucocorticoid in peripheral blood of the oral cancer group were higher than those in benign oral tumor group (p<0.01). We also examined whether associations observed between biobehavioral measures and circulating blood catecholamine and glucocorticoid levels extended to other compartments in the oral cancer group. Conclusions These findings suggest that stress hormones may affect oral cancer behavior by influencing the tumor micro-environment though the circulating blood.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Furthermore, besides cancer cells, stromal cells in the tumor microenvironment could also be affected by the nervous system [7] [8]. Studies of ovarian cancer have demonstrated that NE/E may contribute to tumor progression by promoting angiogenesis [9]. By a large-scale cDNA transfection screening, our previous study revealed that many neurotransmitter receptor-related genes are closely associated with cancer cell proliferation and survival [10]. "
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    ABSTRACT: Monoamine oxidase A (MAOA), a catecholamine neurotransmitter degrading enzyme, is closely associated with neurological and psychiatric disorders. However, its role in cancer progression remains unknown. Hepatocellular carcinoma (HCC) tissue arrays (n=254) were used to investigate the correlation between MAOA expression and clinicopathological findings. In vitro invasion and anoikis assays, and in vivo intrahepatic and lung metastasis models were used to determine the role of MAOA in HCC metastasis. Quantitative real-time PCR, western blotting, immunohistochemical staining and HPLC analysis were performed to uncover the mechanism of MAOA in HCC. We found that MAOA expression was significantly downregulated in 254 clinical HCC samples and was closely correlated with cancer vasoinvasion, metastasis and poor prognoses. We then demonstrated that MAOA suppressed norepinephrine/epinephrine (NE/E)-induced HCC invasion and anoikis inhibition, and uncovered that the effects of NE/E on HCC behaviors were primarily mediated through alpha 1A (ADRA1A) and beta 2 adrenergic receptors (ADRB2). In addition to the canonical signaling pathway, which is mediated via adrenergic receptors (ADRs), we found that ADR-mediated EGFR transactivation was also involved in NE-induced HCC invasion and anoikis inhibition. Notably, we found that MAOA could synergize with EGFR inhibitors or ADR antagonists to abrogate NE-induced HCC behaviors. Taken together, the results of our study may provide insights into the application of MAOA as a novel predictor of clinical outcomes and indicate that increasing MAOA expression or enzyme activity may be a new approach that can be used for HCC treatment.
    Full-text · Article · Mar 2014 · Journal of Hepatology
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    • "Anti-apoptosis Tumour growth Angiogenesis Migration invasion Propranolol [24] [25] [36] [57] [61] [99] [100] "
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    ABSTRACT: β-Adrenoceptors are broadly distributed in various tissues of the body. Stress hormones regulate a panel of important physiological functions and disease states including cancer. Nicotine and its derivatives could stimulate the release of stress hormones from cancer cells, leading to the promotion of cancer development. β-blockers have been widely used to control hypertension for decades. Recently, these agents could have significant implications in cancer therapy through blockade of adrenoceptors in tumor tissues. In this review, we summarize recent advancements about the influence of stress hormones, nicotine and β-adrenoceptors on cancer cell proliferation, apoptosis, invasion and metastasis, and also tumor vasculature normalization. Relevant signal pathways and potential value of β-blockers in the treatment of cancer are also discussed in this review.
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