The SGK1 inhibitor SI113 induces autophagy, apoptosis, and endoplasmic reticulum stress in endometrial cancer cells.
Endometrial cancer is often characterized by PI3K/AKT pathway deregulation. Recently it has been suggested that SGK1, a serine/threonine protein kinase that shares structural and functional similarities with the AKT family, might play a role in cancer, since its expression and/or activity has been found to be deregulated in different human tumors. However, the role of SGK1 in endometrial cancer has been poorly investigated. Here, we show that SGK1 expression is increased in tissue specimens from neoplastic endometrium. The SGK1 inhibitor SI113 induced a significant reduction of endometrial cancer cells viability, measured by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. This effect was associated to the increase of autophagy, as revealed by the increase of the markers LC3B-II and beclin I, detected by both immunofluorescence and western blot analysis. SI113 treatment caused also apoptosis of endometrial cancer cells, evidenced by the cleavage of the apoptotic markers PARP and Caspase-9. Intriguingly, these effects were associated to the induction of endoplasmic reticulum stress markers GRP78 and CHOP evaluated by both Real-Time RT-PCR and Western Blot analysis. Increased expression of SGK1 in endometrial cancer tissues suggest a role for SGK1 in this type of cancer, as reported for other malignancies. Moreover, the efficacy of SI113 in affecting endometrial cancer cells viability, possibly via endoplasmic reticulum stress activation, identifies SGK1 as an attractive molecular target for new tailored therapeutic intervention for the treatment of endometrial cancer.
Department of Medical and Translational Sciences of the University of Naples "Federico II" & URT dell'Istituto di Endocrinologia e Oncologia Sperimentale 'Gaetano Salvatore', Consiglio Nazionale delle Ricerche, Naples, Italy.
Domenico
D
Conza
Department of Medical and Translational Sciences of the University of Naples "Federico II" & URT dell'Istituto di Endocrinologia e Oncologia Sperimentale 'Gaetano Salvatore', Consiglio Nazionale delle Ricerche, Naples, Italy.
Paola
P
Mirra
Istituto di Endocrinologia e Oncologia Sperimentale 'Gaetano Salvatore', Consiglio Nazionale delle Ricerche, Naples, Italy.
Gaetano
G
Calì
Department of Medical and Translational Sciences of the University of Naples "Federico II" & URT dell'Istituto di Endocrinologia e Oncologia Sperimentale 'Gaetano Salvatore', Consiglio Nazionale delle Ricerche, Naples, Italy.
Teresa
T
Tortora
Department of Advanced Biomedical Sciences, University "Federico II", Naples, Italy.
Luigi
L
Insabato
Department of Medical and Translational Sciences of the University of Naples "Federico II" & URT dell'Istituto di Endocrinologia e Oncologia Sperimentale 'Gaetano Salvatore', Consiglio Nazionale delle Ricerche, Naples, Italy.
Francesca
F
Fiory
Department of Farmacia, University of Genova, Genova, Italy.
Silvia
S
Schenone
Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
Rosario
R
Amato
Department of Medical and Translational Sciences of the University of Naples "Federico II" & URT dell'Istituto di Endocrinologia e Oncologia Sperimentale 'Gaetano Salvatore', Consiglio Nazionale delle Ricerche, Naples, Italy.
Francesco
F
Beguinot
Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
Nicola
N
Perrotti
Department of Medical and Translational Sciences of the University of Naples "Federico II" & URT dell'Istituto di Endocrinologia e Oncologia Sperimentale 'Gaetano Salvatore', Consiglio Nazionale delle Ricerche, Naples, Italy.
Luca
http://orcid.org/0000-0002-8496-3538
L
Ulianich
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1 / Q000378:metabolism; D016022:Case-Control Studies; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D000970:Antineoplastic Agents; D000071186:Beclin-1; D053453:Caspase 9; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D017874:Immediate-Early Proteins; D008869:Microtubule-Associated Proteins; D011065:Poly(ADP-ribose) Polymerases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D051742:Transcription Factor CHOP; D000099184:Serum-Glucocorticoid Regulated Kinases; C491997:BECN1 protein, human; C497249:DDIT3 protein, human; C000717247:HSPA5 protein, human; C502070:MAP1LC3B protein, human; C000603764:SI113 compound; C506433:CASP9 protein, human
SGK1; endometrial cancer; endoplasmic reticulum stress