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1.
Redox Biol ; 67: 102931, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37866161

RESUMEN

Cancer cells frequently exhibit aberrant redox homeostasis and adaptation to oxidative stress. Hence abrogation of redox adaptation in cancer cells can be exploited for therapeutic benefit. Here we report SGK3 functions as an anti-oxidative factor to promote cell growth and drug resistance in cervical cancers harboring PIK3CA helical domain mutations. Mechanistically, SGK3 is activated upon oxidative stress and exerts anti-ROS activity by stabilizing and activating the antioxidant enzyme catalase. SGK3 interacts with and phosphorylates catalase, promoting its tetrameric state and activity. Meanwhile, SGK3 phosphorylates GSK3ß and protects catalase from GSK3ß-ß-TrCP mediated ubiquitination and proteasomal degradation. Furthermore, SGK3 inhibition not only potentiates CDK4/6 inhibitor Palbociclib-mediated cytotoxicity, but also overcomes cisplatin resistance through ROS-mediated mechanisms. These data uncover the role of SGK3 in maintaining redox homeostasis and suggest that the SGK3-catalase antioxidant signaling axis may be therapeutically targeted to improve treatment efficacy for cervical cancers carrying PIK3CA helical domain mutations.


Asunto(s)
Proteínas Serina-Treonina Quinasas , Neoplasias del Cuello Uterino , Femenino , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Antioxidantes , Glucógeno Sintasa Quinasa 3 beta , Catalasa , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo
2.
Redox Biol ; 24: 101225, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31136958

RESUMEN

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.


Asunto(s)
Proteínas Inmediatas-Precoces/genética , Oxidación-Reducción , Proteínas Serina-Treonina Quinasas/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Inmediatas-Precoces/metabolismo , Melatonina/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Especies Reactivas de Oxígeno/metabolismo , Neoplasias del Cuello Uterino/patología
3.
EBioMedicine ; 43: 225-237, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30898650

RESUMEN

BACKGROUND: While PARP inhibitors and CDK4/6 inhibitors, the two classes of FDA-approved agents, have shown promising clinical benefits, there is an urgent need to develop new therapeutic strategies to improve clinical response. Meanwhile, extending the utility of these inhibitors beyond their respective molecularly defined cancer types is challenging and will likely require biomarkers predictive of treatment response especially when used in a combination drug development setting. METHODS: The effects of PARP inhibitor Olaparib and CDK4/6 inhibitor Palbociclib on ovarian cancer cells lines including those of high-grade serous histology were examined in vitro and in vivo. We investigated the molecular mechanism underlying the synergistic effects of drug combination. FINDINGS: We show for the first time that combining PARP and CDK4/6 inhibition has synergistic effects against MYC overexpressing ovarian cancer cells both in vitro and in vivo. Mechanistically, we find that Palbociclib induces homologous recombination (HR) deficiency through downregulation of MYC-regulated HR pathway genes, causing synthetic lethality with Olaparib. We further demonstrate that MYC expression determines sensitivity to combinatorial treatment with Olaparib and Palbociclib. INTERPRETATION: Our data provide a rationale for clinical evaluation of therapeutic synergy of these two classes of inhibitors in ovarian cancer patients whose tumors show high MYC expression and who do not respond to PARP inhibitors or CDK4/6 inhibitors monotherapies. FUND: This work was supported by the National Natural Science Foundation of China [81672575, 81874111, 81472447 to HC; 81572586 and 81372853 to PL], and the Liaoning Provincial Key Basic Research Program for Universities [LZ2017002 to HC].


Asunto(s)
Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genes myc , Neoplasias Ováricas/genética , Ftalazinas/farmacología , Piperazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Piridinas/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Inestabilidad Genómica , Humanos , Ratones , ARN Interferente Pequeño/genética , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Oncol Rep ; 41(5): 2667-2678, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30896884

RESUMEN

Uterine serous carcinoma (USC) is a subtype of endometrial cancer. Compared with endometrial endometroid carcinoma, the majority of USC cases are more aggressive. Cyclin-dependent kinase inhibitor 2A (P16INK4A) is a canonical tumor suppressor that blocks cell cycle progression; however, P16INK4A is overexpressed in USC. The aim of the present study was to determine the role of P16INK4A in P16INK4A­positive endometrial cancer, with the hope of elucidating a novel therapeutic approach for this type of malignancy. A total of 2 endometrial cancer cell lines, ETN­1 and EFE­184, were selected for further investigation, due to them being known to express high levels of P16INK4A. Using short hairpin RNA targeting P16INK4A, P16INK4A was downregulated in these cancer cell lines. Cell viability and migration were examined via 2D/3D clonogenic and wound healing assays. Subsequently, GSK­J4, a histone demethylase inhibitor, was employed to deplete P16INK4A in these cancer cell lines and an ex vivo culture system of a patient­derived xenograft (PDX) endometrial tumor sample. Following P16INK4A knockdown, the proliferation and migration of ETN­1 and EFE­184 cells markedly declined. When exposed to GSK­J4, the levels of KDM6B and P16INK4A were almost completely abrogated, and the cell viability was significantly reduced in these cell lines and the ex vivo­cultured PDX tumor explants. The association between the levels of P16INK4A, lysine demethylase 6B (KDM6B) and the methylation status of histone 3 lysine 27 (H3K27) in these cell lines and the human USC tumor sample was also demonstrated. P16INK4A appears to be oncogenic in a number of endometrial cancer cell lines. The level of P16INK4A is associated with the methylation status of H3K27. Increased methylation of H3K27 coexists with downregulation of KDM6B and, subsequently, P16INK4A, which reduces cell proliferation and invasiveness in endometrial cancer. The observations of the present study may enable the development of a novel therapeutic strategy for P16INK4A­positive endometrial cancer, particularly USC.


Asunto(s)
Antineoplásicos/farmacología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Cistadenocarcinoma Seroso/patología , Metilación de ADN/efectos de los fármacos , Neoplasias Endometriales/patología , Adulto , Anciano , Animales , Antineoplásicos/uso terapéutico , Benzazepinas/farmacología , Benzazepinas/uso terapéutico , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/genética , Regulación hacia Abajo , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Endometrio/patología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Técnicas de Silenciamiento del Gen , Células HEK293 , Histonas/metabolismo , Humanos , Histona Demetilasas con Dominio de Jumonji/antagonistas & inhibidores , Histona Demetilasas con Dominio de Jumonji/metabolismo , Ratones , Persona de Mediana Edad , Invasividad Neoplásica/genética , Invasividad Neoplásica/prevención & control , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , ARN Interferente Pequeño/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Cancer Lett ; 440-441: 54-63, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30315845

RESUMEN

Selective phosphatidylinositol 3 kinase (PI3K) inhibitors are being actively tested in clinical trials for ERα-positive (ER+) breast cancer due to the presence of activating PIK3CA mutations. However, recent studies have revealed that increased ERα transcriptional activity limits the efficacy of PI3K inhibitor monotherapy for ER + breast cancers. Herein, we report the identification of BTF3 as an oncogenic transcription factor that regulates ERα expression in luminal breast cancers. Our TCGA analysis reveals high expression levels of BTF3 in luminal/ER + breast cancer and cell line models harboring ERα overexpression. Concordantly, BTF3 expression is highly and strongly associated with ESR1 expression in multiple breast cancer cohorts. We further show that BTF3 promotes the proliferation, survival and migration of ER + breast cancer cells by modulating ESR1 expression and ERα-dependent transcription. Moreover, BTF3 knockdown sensitizes ER + breast cancer cells to the PI3Kα inhibitor BYL-719 in both in vitro and in vivo models. Together, our findings highlight a novel role of BTF3 in modulation of ERα-dependent transcriptional activity and its potential as a predictive marker for the response to PI3K-targeted therapy in ER + breast cancer.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Receptor alfa de Estrógeno/genética , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , División Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Receptor alfa de Estrógeno/biosíntesis , Femenino , Fase G2/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Tiazoles/farmacología , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética , Ensayos Antitumor por Modelo de Xenoinjerto
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