期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 120, 期 5, 页码 1515-1523出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI40802
关键词
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资金
- NCI [F31CA126474, CA101642]
- NIH [CA110793, CA109298, CA-104825, A152737]
- University of Texas MD Anderson Cancer Center Ovarian Cancer Spore [P50 CA083639]
- Zarrow Foundation
- EIF Foundation
- Betty Ann Asche Murray Distinguished Professorship
- Blanton-Davis Ovarian Cancer Research Program
- Marcus Foundation
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.
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