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

作者:Sood Anil K*; Armaiz Pena Guillermo N; Haider Jyotsnabaran; Nick Alpa M; Stone Rebecca L; Hu Wei; Carroll Amy R; Spannuth Whitney A; Deavers Michael T; Allen Julie K; Han Liz Y; Kamat Aparna A; Shahzad Mian M K; McIntyre Bradley W; Diaz Montero Claudia M; Jennings Nicholas B; Lin Yvonne G; Merritt William M; DeGeest Koen; Vivas Mejia Pablo E; Lopez Berestein Gabriel; Schaller Michael D; Cole Steven W; Lutgendorf Susan K
来源:Journal of Clinical Investigation, 2010, 120(5): 1515-1523.
DOI:10.1172/JCI40802

摘要

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.

  • 出版日期2010-5