Abstract
Original language | English |
---|---|
Pages (from-to) | 6370-6386 |
Number of pages | 17 |
Journal | Oncogene |
Volume | 39 |
Issue number | 40 |
DOIs | |
Publication status | Published - 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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Serum- and glucocorticoid- inducible kinase 2, SGK2, is a novel autophagy regulator and modulates platinum drugs response in cancer cells. / Ranzuglia, V.; Lorenzon, I.; Pellarin, I.; Sonego, M.; Dall’Acqua, A.; D’Andrea, S.; Lovisa, S.; Segatto, I.; Coan, M.; Polesel, J.; Serraino, D.; Sabatelli, P.; Spessotto, P.; Belletti, B.; Baldassarre, G.; Schiappacassi, M.
In: Oncogene, Vol. 39, No. 40, 2020, p. 6370-6386.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Serum- and glucocorticoid- inducible kinase 2, SGK2, is a novel autophagy regulator and modulates platinum drugs response in cancer cells
AU - Ranzuglia, V.
AU - Lorenzon, I.
AU - Pellarin, I.
AU - Sonego, M.
AU - Dall’Acqua, A.
AU - D’Andrea, S.
AU - Lovisa, S.
AU - Segatto, I.
AU - Coan, M.
AU - Polesel, J.
AU - Serraino, D.
AU - Sabatelli, P.
AU - Spessotto, P.
AU - Belletti, B.
AU - Baldassarre, G.
AU - Schiappacassi, M.
N1 - Export Date: 19 February 2021 CODEN: ONCNE Correspondence Address: Baldassarre, G.; Division of Molecular Oncology, Italy; email: gbaldassarre@cro.it Correspondence Address: Schiappacassi, M.; Division of Molecular Oncology, Italy; email: mschiappacassi@cro.it Chemicals/CAS: carboplatin, 41575-94-4; cisplatin, 15663-27-1, 26035-31-4, 96081-74-2; paclitaxel, 33069-62-4; protein serine threonine kinase; proton transporting adenosine triphosphate synthase, 37205-63-3; benzoic acid, 532-32-1, 582-25-2, 65-85-0, 766-76-7; ATP6V1H protein, human; Benzoates; Bridged Bicyclo Compounds, Heterocyclic; Carboplatin; Cisplatin; GSK 650394; Immediate-Early Proteins; Paclitaxel; Protein Kinase Inhibitors; Protein-Serine-Threonine Kinases; RNA, Small Interfering; serum-glucocorticoid regulated kinase; Vacuolar Proton-Translocating ATPases Manufacturers: Teva, Italy Funding details: Ministero della Salute, RF-2010-2309704, RF-2016-02361040, RF-2016-02361041 Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC, 18171 Funding details: Regione Autonoma Friuli Venezia Giulia, FVG, 5 × 1000 CRO Funding text 1: Acknowledgements We thank Dr William Hahn and David Root for SGK2 vector (through Addgene), Dr Tamotsu Yoshimori for ptfLC3 vectors (through Addgene), Dr Roberta Maestro for pLPC vector and Laura Cesaratto and Sara Benevol for technical support. We are grateful to all members of our lab for helpful and stimulating discussions. This work was supported by grants from Ministero della Salute (RF-2010-2309704 and RF-2016-02361040), Regione Friuli Venezia Giulia (Tichep Grant) and 5 × 1000 CRO to GB; grants from 5 × 1000 CRO Intramural Young Investigator and from Ministero della Salute (RF-2016-02361041) to MSo. IS was supported by an AIRC biannual Fellowship (# 18171). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - carboplatin
KW - cisplatin
KW - paclitaxel
KW - platinum complex
KW - protein serine threonine kinase
KW - proton transporting adenosine triphosphate synthase
KW - serum and glucocorticoid inducible kinase 2
KW - unclassified drug
KW - antineoplastic agent
KW - ATP6V1H protein, human
KW - benzoic acid
KW - fused heterocyclic rings
KW - GSK 650394
KW - immediate early protein
KW - protein kinase inhibitor
KW - serum-glucocorticoid regulated kinase
KW - small interfering RNA
KW - acidification
KW - Article
KW - autophagy (cellular)
KW - cancer cell
KW - cancer resistance
KW - cell survival
KW - controlled study
KW - drug response
KW - enzyme binding
KW - enzyme inhibition
KW - enzyme phosphorylation
KW - female
KW - gene silencing
KW - gene targeting
KW - genetic screening
KW - human
KW - human cell
KW - lysosome
KW - ovary carcinoma
KW - priority journal
KW - SGK2 gene
KW - apoptosis
KW - autophagy
KW - drug effect
KW - drug resistance
KW - genetics
KW - metabolism
KW - ovary tumor
KW - pathology
KW - phosphorylation
KW - tumor cell line
KW - Antineoplastic Combined Chemotherapy Protocols
KW - Apoptosis
KW - Autophagy
KW - Benzoates
KW - Bridged Bicyclo Compounds, Heterocyclic
KW - Carboplatin
KW - Carcinoma, Ovarian Epithelial
KW - Cell Line, Tumor
KW - Cell Survival
KW - Cisplatin
KW - Drug Resistance, Neoplasm
KW - Female
KW - Humans
KW - Immediate-Early Proteins
KW - Ovarian Neoplasms
KW - Paclitaxel
KW - Phosphorylation
KW - Protein Kinase Inhibitors
KW - Protein-Serine-Threonine Kinases
KW - RNA, Small Interfering
KW - Vacuolar Proton-Translocating ATPases
U2 - 10.1038/s41388-020-01433-6
DO - 10.1038/s41388-020-01433-6
M3 - Article
VL - 39
SP - 6370
EP - 6386
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 40
ER -