TY - JOUR
T1 - Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis
AU - Sood, Anil K.
AU - Armaiz-Pena, Guillermo N.
AU - Halder, Jyotsnabaran
AU - Nick, Alpa M.
AU - Stone, Rebecca L.
AU - Hu, Wei
AU - Carroll, Amy R.
AU - Spannuth, Whitney A.
AU - Deavers, Michael T.
AU - Allen, Julie K.
AU - Han, Liz Y.
AU - Kamat, Aparna A.
AU - Shahzad, Mian M.K.
AU - McIntyre, Bradley W.
AU - Diaz-Montero, Claudia M.
AU - Jennings, Nicholas B.
AU - Lin, Yvonne G.
AU - Merritt, William M.
AU - DeGeest, Koen
AU - Vivas-Mejia, Pablo E.
AU - Lopez-Berestein, Gabriel
AU - Schaller, Michael D.
AU - Cole, Steven W.
AU - Lutgendorf, Susan K.
PY - 2010/5/3
Y1 - 2010/5/3
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI40802
DO - 10.1172/JCI40802
M3 - Article
C2 - 20389021
AN - SCOPUS:77951863320
SN - 0021-9738
VL - 120
SP - 1515
EP - 1523
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -