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

J Clin Invest. doi:10.1172/JCI40802.
Copyright © 2010, The American Society for Clinical Investigation.
Research Article
Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis

Anil K. Sood1,2,3, Guillermo N. Armaiz-Pena1, Jyotsnabaran Halder1, Alpa M. Nick1, Rebecca L. Stone1, Wei Hu1, Amy R. Carroll1, Whitney A. Spannuth1, Michael T. Deavers4, Julie K. Allen1, Liz Y. Han1, Aparna A. Kamat1, Mian M.K. Shahzad1, Bradley W. McIntyre5, Claudia M. Diaz-Montero5, Nicholas B. Jennings1, Yvonne G. Lin1, William M. Merritt1, Koen DeGeest6, Pablo E. Vivas-Mejia7, Gabriel Lopez-Berestein2,3,7, Michael D. Schaller8, Steven W. Cole9 and Susan K. Lutgendorf6,10

1Department of Gynecologic Oncology,
2Department of Cancer Biology,
3Center for RNA Interference and Non-Coding RNA,
4Department of Pathology,
5Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
6Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Iowa, Iowa City, Iowa, USA.
7Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
8Department of Biochemistry, West Virginia University, Morgantown, West Virginia, USA.
9Department of Medical Oncology Hematology, UCLA, Los Angeles, California, USA.
10Departments of Psychology and Urology and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA.

Address correspondence to: Anil K. Sood, Departments of Gynecologic Oncology and Cancer Biology, UT MD Anderson Cancer Center, 1155 Herman Pressler, Unit 1362, Houston, Texas 77030, USA. Phone: 713.745.5266; Fax: 713.792.7586; E-mail: asood@mdanderson.org.

Published April 12, 2010
Received for publication August 12, 2009, and accepted in revised form February 3, 2010.

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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