Inhibition of SGK1 confers vulnerability to redox dysregulation in cervical cancer
Min Wang,
Yijue Xue,
Lanlin Shen,
Pan Qin,
Xiaolin Sang,
Zhiwei Tao,
Jingyan Yi,
Jia Wang,
Pixu Liu,
Hailing Cheng
Affiliations
Min Wang
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China
Yijue Xue
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China
Lanlin Shen
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China
Pan Qin
Faculty of Electronic Information and Electrical Engineering, Dalian University of Technology, Dalian, Liaoning, China
Xiaolin Sang
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China
Zhiwei Tao
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China
Jingyan Yi
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China
Jia Wang
Department of Breast Surgery, Institute of Breast Disease, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China; Corresponding author. The Second Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, Liaoning, China.
Pixu Liu
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China; Corresponding author. Institute of Cancer Stem Cell, Dalian Medical University, 9 West Lv Shun Nan Road, Dalian, Liaoning, China.
Hailing Cheng
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, China; Corresponding author. The Second Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, Liaoning, China.
Cervical cancer has poor prognosis and patients are often diagnosed at advanced stages of the disease with limited treatment options. There is thus an urgent need for the discovery of new therapeutic strategies in cervical cancer. The activation of SGK1 has been linked to the development of various cancer types but little is known about the role of SGK1 in cervical cancer and its potential as a therapeutic target. Here we report that SGK1 is an antioxidative factor that promotes survival of cervical cancer cells. Gene set enrichment analysis of RNA-Seq data reveals a strong inverse association between SGK1 and oxidative phosphorylation. Consistently, inhibition of SGK1 via siRNA or pharmacological inhibitor GSK650394 induces ROS and cytotoxicity upon H2O2 stress. Further analysis of clinical data associates SGK1 with gene expression signatures regulated by the antioxidant transcription factor NRF2 in cervical cancer. Mechanistically, SGK1 activation exerts antioxidant effect through induction of c-JUN-dependent NRF2 expression and activity. Importantly, we find that inhibition of SGK1 confers vulnerability to melatonin as a pro-oxidant, resulting in ROS over-accumulation and consequently enhanced cell cytotoxicity. We further demonstrate that combined use of GSK650394 and melatonin yields substantial regression of cervical tumors in vivo. This work opens new perspectives on the potential of SGK1 inhibitors as sensitizing agents to enable the design of therapeutically redox-modulating strategies against cervical cancer. Keywords: Cervical cancer, SGK1, NRF2, ROS, Melatonin
