Sustained Adrenergic Activation of YAP1 Induces Anoikis Resistance in Cervical Cancer Cells
Yang Li,
Shanshan Yang,
Nouara C. Sadaoui,
Wei Hu,
Santosh K. Dasari,
Lingegowda S. Mangala,
Yunjie Sun,
Shuangtao Zhao,
Linghua Wang,
Yuan Liu,
Lois M. Ramondetta,
Ke Li,
Chong Lu,
Yu Kang,
Steve W. Cole,
Susan K. Lutgendorf,
Anil K. Sood
Affiliations
Yang Li
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Shanshan Yang
Department of Gynecologic Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, China
Nouara C. Sadaoui
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Wei Hu
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Santosh K. Dasari
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Lingegowda S. Mangala
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Yunjie Sun
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Shuangtao Zhao
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Linghua Wang
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Yuan Liu
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Lois M. Ramondetta
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Ke Li
Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
Chong Lu
Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
Yu Kang
Department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai, China
Steve W. Cole
Cousins Center for Psychoneuroimmunology and Department of Psychiatry and Biobehavioral Sciences, Division of Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
Susan K. Lutgendorf
Department of Psychological & Brain Sciences, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Department of Urology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA
Anil K. Sood
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Corresponding author
Summary: Chronic stress-related hormones modulate tumor pathogenesis at multiple levels; however, the molecular pathways involved in stress and cervical cancer progression are not well understood. We established a preclinical orthotopic mouse model of cervical cancer and used the model to show that daily restraint stress increased tumor growth and metastatic tumor burden. Exposure to norepinephrine significantly protected cervical cancer cells from anoikis. We demonstrated that YAP1 was dephosphorylated and translocated from the cytoplasm to the nucleus by norepinephrine, a process initiated by ADRB2/cAMP/protein kinase A activation. Furthermore, anoikis resistance and YAP1 activation induced by norepinephrine could be rescued by a broad β-adrenergic receptor antagonist, propranolol. Collectively, our results provide a pivotal molecular pathway for disrupting pro-tumor neuroendocrine signaling in cervical cancer.
