Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis.
Title | Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Sood 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 |
Journal | J Clin Invest |
Volume | 120 |
Issue | 5 |
Pagination | 1515-23 |
Date Published | 2010 May |
ISSN | 1558-8238 |
Keywords | Actins, 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. |
DOI | 10.1172/JCI40802 |
Alternate Journal | J. Clin. Invest. |
PubMed ID | 20389021 |
PubMed Central ID | PMC2860925 |
Grant List | A152737 / / 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 |