Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis.
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.
Sood
Anil K
AK
Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. asood@mdanderson.org
Armaiz-Pena
Guillermo N
GN
Halder
Jyotsnabaran
J
Nick
Alpa M
AM
Stone
Rebecca L
RL
Hu
Wei
W
Carroll
Amy R
AR
Spannuth
Whitney A
WA
Deavers
Michael T
MT
Allen
Julie K
JK
Han
Liz Y
LY
Kamat
Aparna A
AA
Shahzad
Mian M K
MM
McIntyre
Bradley W
BW
Diaz-Montero
Claudia M
CM
Jennings
Nicholas B
NB
Lin
Yvonne G
YG
Merritt
William M
WM
DeGeest
Koen
K
Vivas-Mejia
Pablo E
PE
Lopez-Berestein
Gabriel
G
Schaller
Michael D
MD
Cole
Steven W
SW
Lutgendorf
Susan K
SK
D000199:Actins / Q000378:metabolism; D018663:Adrenergic Agents / Q000378:metabolism*; D000818:Animals; D023102:Anoikis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004837:Epinephrine / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009638:Norepinephrine / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010766:Phosphorylation
D000199:Actins; D018663:Adrenergic Agents; D051416:Focal Adhesion Protein-Tyrosine Kinases; D009638:Norepinephrine; D004837:Epinephrine
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