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

TitleAdrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis.
Publication TypeJournal Article
Year of Publication2010
AuthorsSood AK, Armaiz-Pena GN, Halder J, Nick AM, Stone RL, Hu W, Carroll AR, Spannuth WA, Deavers MT, Allen JK, Han LY, Kamat AA, Shahzad MMK, McIntyre BW, Diaz-Montero CM, Jennings NB, Lin YG, Merritt WM, DeGeest K, Vivas-Mejia PE, Lopez-Berestein G, Schaller MD, Cole SW, Lutgendorf SK
JournalJ Clin Invest
Volume120
Issue5
Pagination1515-23
Date Published2010 May
ISSN1558-8238
KeywordsActins, Adrenergic Agents, Animals, Anoikis, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Epinephrine, Female, Focal Adhesion Protein-Tyrosine Kinases, Humans, Mice, Mice, Nude, Norepinephrine, Ovarian Neoplasms, Phosphorylation
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.

DOI10.1172/JCI40802
Alternate JournalJ. Clin. Invest.
PubMed ID20389021
PubMed Central IDPMC2860925
Grant ListA152737 / / PHS HHS / United States
CA-104825 / CA / NCI NIH HHS / United States
CA109298 / CA / NCI NIH HHS / United States
CA110793 / CA / NCI NIH HHS / United States
F31CA126474 / CA / NCI NIH HHS / United States
P50 CA083639 / CA / NCI NIH HHS / United States
R01 CA109298 / CA / NCI NIH HHS / United States
R01 CA109298-01A1 / CA / NCI NIH HHS / United States
R01 CA110793 / CA / NCI NIH HHS / United States
R01 CA110793-01 / CA / NCI NIH HHS / United States
R01 CA140933 / CA / NCI NIH HHS / United States
T32CA101642 / CA / NCI NIH HHS / United States