Inhibition of SGK1 confers vulnerability to redox dysregulation in cervical cancer

Redox Biol. 2019 Jun;24:101225. doi: 10.1016/j.redox.2019.101225. Epub 2019 May 20.

Abstract

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; Melatonin; NRF2; ROS; SGK1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immediate-Early Proteins / genetics*
  • Immediate-Early Proteins / metabolism
  • Melatonin / metabolism
  • Mice
  • NF-E2-Related Factor 2 / genetics
  • Oxidation-Reduction*
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Reactive Oxygen Species / metabolism
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / metabolism*
  • Uterine Cervical Neoplasms / pathology

Substances

  • Antioxidants
  • Immediate-Early Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Proto-Oncogene Proteins c-jun
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Melatonin