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Int J Cancer ; 145(6): 1635-1647, 2019 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-31228268


Uterine serous carcinoma (USC) is a highly aggressive histological subtype of endometrial cancers harboring highly metastatic and chemoresistant features. Our previous study showed that STAT1 is highly expressed in USC and acts as a key molecule that is positively correlated with tumor progression, but it remains unclear whether STAT1 is relevant to the malicious chemorefractory nature of USC. In the present study, we investigated the regulatory role of STAT1 toward platinum-cytotoxicity in USC. STAT1 suppression sensitized USC cells to increase cisplatin-mediated apoptosis (p < 0.001). Furthermore, phosphorylation of STAT1 was prominently observed on serine-727 (pSTAT1-Ser727), but not on tyrosine-701, in the nucleus of USC cells treated with cisplatin. Mechanistically, the inhibition of pSTAT1-Ser727 by dominant-negative plasmid elevated cisplatin-mediated apoptosis by increasing intracellular accumulation of cisplatin through upregulation of CTR1 expression. TBB has an inhibitory effect on casein kinase 2 (CK2), which phosphorylate STAT1 at serine residues. Sequential treatment with TBB and cisplatin on USC cells greatly reduced nuclear pSTAT1-Ser727, enhanced intracellular accumulation of cisplatin, and subsequently increased apoptosis. Tumor load was significantly reduced by combination therapy of TBB and cisplatin in in vivo xenograft models (p < 0.001). Our results collectively suggest that pSTAT1-Ser727 may play a key role in platinum resistance as well as tumor progression in USC. Thus, targeting the STAT1 pathway via CK2 inhibitor can be a novel method for attenuating the chemorefractory nature of USC.

Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Cistadenocarcinoma Seroso/tratamiento farmacológico , Factor de Transcripción STAT1/metabolismo , Serina/metabolismo , Neoplasias Uterinas/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quimioterapia Adyuvante , Cisplatino/farmacología , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Resistencia a Antineoplásicos , Femenino , Xenoinjertos , Humanos , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Fosforilación , Factor de Transcripción STAT1/química , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patología
Cancer Biol Ther ; 15(1): 22-5, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24096267


Sorafenib is an oral multikinase inhibitor targeting Raf and other kinases. The anti-tumor effect of sorafenib is thought to be mediated through its inhibition of the RAS-Raf-Erk pathway, as well as its inhibition of VEGFR and PDGFR. Sorafenib has been effective at treating patients with renal cell carcinoma (RCC). Ovarian clear cell carcinoma (OCCC) is a chemoresistant subtype of ovarian cancer. OCCC is represented by cells with clear cytoplasm that resemble those observed in RCC. Using a microarray database, the gene expression profile of OCCC was similar to that of RCC. The effects of sorafenib against human OCCC are unknown. Therefore, we used sorafenib to treat two patients with recurrent chemoresistant OCCC, and observed good effect in both of them without severe side effects. We believe that sorafenib is an effective agent against OCCC. Given the chemoresistant nature of this tumor, this drug appears to be very valuable.

Adenocarcinoma de Células Claras/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Niacinamida/análogos & derivados , Neoplasias Ováricas/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Niacinamida/uso terapéutico , Sorafenib
J Obstet Gynaecol Res ; 40(1): 263-7, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24033661


Humoral hypercalcemia of malignancy (HHM) is a paraneoplastic syndrome primarily caused by a tumor-producing parathyroid hormone-related protein (PTH-rP). We describe the first reported case of a uterine carcinosarcoma causing HHM. A 70-year-old patient was transferred to our hospital for a uterine tumor accompanied by impaired consciousness. The laboratory tests indicated anemia, malnutrition, elevated serum calcium and elevated PTH-rP. Emergency surgery, including abdominal hysterectomy and bilateral salpingo-oophorectomy, was performed due to uncontrollable uterine bleeding. The pathological diagnosis was carcinosarcoma consisting of pure squamous cell carcinoma in its epithelial component. Postoperatively, chemotherapy with paclitaxel and carboplatin was performed. The patient had recurrent tumors at the para-aortic lymph nodes 11 months after the initial surgery and underwent a pelvic and para-aortic lymphadenectomy, which removed all of the recurrent tumors.

Carcinoma de Células Escamosas/fisiopatología , Carcinosarcoma/fisiopatología , Endometrio/patología , Hipercalcemia/etiología , Síndromes Paraneoplásicos/etiología , Neoplasias Uterinas/fisiopatología , Útero/patología , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Carcinosarcoma/tratamiento farmacológico , Carcinosarcoma/patología , Carcinosarcoma/cirugía , Quimioterapia Adyuvante , Femenino , Humanos , Hipercalcemia/prevención & control , Histerectomía , Ovariectomía , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Síndromes Paraneoplásicos/prevención & control , Salpingectomía , Resultado del Tratamiento , Hemorragia Uterina/etiología , Hemorragia Uterina/prevención & control , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/patología , Neoplasias Uterinas/cirugía , Útero/cirugía
Cancer Sci ; 101(12): 2658-63, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21040214


The purpose of this study was to investigate a new modality of therapy against ovarian clear cell carcinoma (OCCC), a chemoresistant subtype of ovarian cancer. Microarray datasets of ovarian cancer cell lines and cancer tissues were analyzed using bioinformatic tools. The gene expression profile of OCCC was similar to that of renal cell carcinoma (RCC). This similarity was at least partially due to hepatocyte nuclear factor 1 pathway activation common to both malignancies. In addition, oncogenic pathway alterations were characteristic of OCCC including hypoxia inducible factor 1 alpha subunit and relatively high Ras activities. Therefore, we predicted that the multi-kinase inhibitor sorafenib, which is approved for RCC and suppresses Ras activity, would also be effective against OCCC. Orally administered sorafenib (40 mg/kg per day) significantly inhibited tumor growth in nude mice when it was given after inoculation with the OCCC cell line RMG-2 (P = 0.002). Furthermore, sorafenib significantly reduced tumor size when it was administered to established RMG-2 tumors (P = 0.0002), while intraperitoneal injection of cisplatin (5 mg/kg per week) did not. In conclusion, the prominent anti-tumor effect of sorafenib against OCCC indicates that sorafenib is a promising candidate drug and supports the need for clinical trials using sorafenib against OCCC. This report demonstrates a method to utilize genome-wide information to facilitate translational research for treatments against less common subtypes of cancers.

Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/genética , Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Piridinas/uso terapéutico , Animales , Femenino , Perfilación de la Expresión Génica , Humanos , Ratones , Ratones Desnudos , Niacinamida/análogos & derivados , Análisis de Secuencia por Matrices de Oligonucleótidos , Compuestos de Fenilurea , Sorafenib , Ensayos Antitumor por Modelo de Xenoinjerto
Mol Cancer Res ; 7(2): 210-20, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19208743


Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein, we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary serous epithelial ovarian cancer and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using small interfering RNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in ovarian cancer and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule-stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA cross-linking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility, and proliferation but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function.

Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Paclitaxel/uso terapéutico , Factor de Transcripción YY1/genética , Sitios de Unión , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cisplatino/uso terapéutico , Hibridación Genómica Comparativa , Docetaxel , Factores de Transcripción E2F/genética , Factores de Transcripción E2F/metabolismo , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/mortalidad , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/mortalidad , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Taxoides/uso terapéutico , Cicatrización de Heridas , Factor de Transcripción YY1/antagonistas & inhibidores