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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Apoptosis / drug effects
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Autophagy / drug effects*
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Benzoates / pharmacology
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Benzoates / therapeutic use
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
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Carboplatin / pharmacology
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Carboplatin / therapeutic use
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Carcinoma, Ovarian Epithelial / drug therapy*
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Carcinoma, Ovarian Epithelial / genetics
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Carcinoma, Ovarian Epithelial / pathology
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Cell Line, Tumor
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Cell Survival / drug effects
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Cisplatin / pharmacology
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Cisplatin / therapeutic use
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Drug Resistance, Neoplasm / drug effects
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Female
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Humans
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Immediate-Early Proteins / antagonists & inhibitors
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism*
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / pathology
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Paclitaxel / pharmacology
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Paclitaxel / therapeutic use
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Phosphorylation / drug effects
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Phosphorylation / genetics
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Small Interfering / metabolism
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Vacuolar Proton-Translocating ATPases / metabolism
Substances
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Benzoates
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Bridged Bicyclo Compounds, Heterocyclic
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Immediate-Early Proteins
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Protein Kinase Inhibitors
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RNA, Small Interfering
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2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid
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Carboplatin
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Protein Serine-Threonine Kinases
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serum-glucocorticoid regulated kinase
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ATP6V1H protein, human
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Vacuolar Proton-Translocating ATPases
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Paclitaxel
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Cisplatin