Serum- and glucocorticoid- inducible kinase 2, SGK2, is a novel autophagy regulator and modulates platinum drugs response in cancer cells

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Abstract

For many tumor types chemotherapy still represents the therapy of choice and many standard treatments are based on the use of platinum (PT) drugs. However, de novo or acquired resistance to platinum is frequent and leads to disease progression. In Epithelial Ovarian Cancer (EOC) patients, PT-resistant recurrences are very common and improving the response to treatment still represents an unmet clinical need. To identify new modulators of PT-sensitivity, we performed a loss-of-function screening targeting 680 genes potentially involved in the response of EOC cells to platinum. We found that SGK2 (Serum-and Glucocorticoid-inducible kinase 2) plays a key role in PT-response. We show here that EOC cells relay on the induction of autophagy to escape PT-induced death and that SGK2 inhibition increases PT sensitivity inducing a block in the autophagy cascade due to the impairment of lysosomal acidification. Mechanistically we demonstrate that SGK2 controls autophagy in a kinase-dependent manner by binding and inhibiting the V-ATPase proton pump. Accordingly, SGK2 phosphorylates the subunit V1H (ATP6V1H) of V-ATPase and silencing or chemical inhibition of SGK2, affects the normal autophagic flux and sensitizes EOC cells to platinum. Hence, we identified a new pathway that links autophagy to the survival of cancer cells under platinum treatment in which the druggable kinase SGK2 plays a central role. Our data suggest that blocking autophagy via SGK2 inhibition could represent a novel therapeutic strategy to improve patients’ response to platinum. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Original languageEnglish
Pages (from-to)6370-6386
Number of pages17
JournalOncogene
Volume39
Issue number40
DOIs
Publication statusPublished - 2020

Keywords

  • carboplatin
  • cisplatin
  • paclitaxel
  • platinum complex
  • protein serine threonine kinase
  • proton transporting adenosine triphosphate synthase
  • serum and glucocorticoid inducible kinase 2
  • unclassified drug
  • antineoplastic agent
  • ATP6V1H protein, human
  • benzoic acid
  • fused heterocyclic rings
  • GSK 650394
  • immediate early protein
  • protein kinase inhibitor
  • serum-glucocorticoid regulated kinase
  • small interfering RNA
  • acidification
  • Article
  • autophagy (cellular)
  • cancer cell
  • cancer resistance
  • cell survival
  • controlled study
  • drug response
  • enzyme binding
  • enzyme inhibition
  • enzyme phosphorylation
  • female
  • gene silencing
  • gene targeting
  • genetic screening
  • human
  • human cell
  • lysosome
  • ovary carcinoma
  • priority journal
  • SGK2 gene
  • apoptosis
  • autophagy
  • drug effect
  • drug resistance
  • genetics
  • metabolism
  • ovary tumor
  • pathology
  • phosphorylation
  • tumor cell line
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis
  • Autophagy
  • Benzoates
  • Bridged Bicyclo Compounds, Heterocyclic
  • Carboplatin
  • Carcinoma, Ovarian Epithelial
  • Cell Line, Tumor
  • Cell Survival
  • Cisplatin
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Immediate-Early Proteins
  • Ovarian Neoplasms
  • Paclitaxel
  • Phosphorylation
  • Protein Kinase Inhibitors
  • Protein-Serine-Threonine Kinases
  • RNA, Small Interfering
  • Vacuolar Proton-Translocating ATPases

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