Inhibition of SGK1 confers vulnerability to redox dysregulation in cervical cancer
| Autor: | Zhiwei Tao, Pan Qin, Hailing Cheng, Min Wang, Jingyan Yi, Xiaolin Sang, Jia Wang, Lanlin Shen, Yijue Xue, Pixu Liu |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
NF-E2-Related Factor 2 Proto-Oncogene Proteins c-jun Clinical Biochemistry Uterine Cervical Neoplasms Apoptosis Disease Protein Serine-Threonine Kinases Biochemistry Antioxidants Immediate-Early Proteins Melatonin Mice 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor Animals Humans Medicine RNA Small Interfering Cytotoxicity lcsh:QH301-705.5 Transcription factor Cervical cancer lcsh:R5-920 urogenital system business.industry Organic Chemistry Cancer medicine.disease Gene Expression Regulation Neoplastic 030104 developmental biology lcsh:Biology (General) Cancer research SGK1 Female RNA Interference Reactive Oxygen Species lcsh:Medicine (General) business Oxidation-Reduction 030217 neurology & neurosurgery Research Paper medicine.drug |
| Zdroj: | Redox Biology, Vol 24, Iss, Pp-(2019) |
| ISSN: | 2213-2317 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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