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.
Anil K. Sood, Guillermo N. Armaiz-Pena, Jyotsnabaran Halder, Alpa M. Nick, Rebecca L. Stone, Wei Hu, Amy R. Carroll, Whitney A. Spannuth, Michael T. Deavers, Julie K. Allen, Liz Y. Han, Aparna A. Kamat, Mian M.K. Shahzad, Bradley W. McIntyre, Claudia M. Diaz-Montero, Nicholas B. Jennings, Yvonne G. Lin, William M. Merritt, Koen DeGeest, Pablo E. Vivas-Mejia, Gabriel Lopez-Berestein, Michael D. Schaller, Steven W. Cole, Susan K. Lutgendorf
Clinical significance of FAK activation in ovarian carcinoma.