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
Abstract
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.