RESUMO
Identification of ovarian cancer patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high-grade ovarian cancer tumors at diagnosis express CIP2A oncoprotein at low levels. Furthermore, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient ovarian cancer cells, we identified reactive oxygen species inducer APR-246, tested previously in ovarian cancer clinical trials. Consistent with CIP2A-deficient ovarian cancer subtype in humans, CIP2A is dispensable for development of MISIIR-Tag-driven mouse ovarian cancer tumors. Nevertheless, CIP2A-null ovarian cancer tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the ovarian cancer cells to APR-246 by inhibition of NF-κB activity. Accordingly, combination of APR-246 and NF-κB inhibitor compounds strongly synergized in killing of CIP2A-positive ovarian cancer cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient ovarian cancer tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.
Assuntos
NF-kappa B , Neoplasias Ovarianas , Animais , Autoantígenos/genética , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , QuinuclidinasRESUMO
Cancer stem cells (CSCs) are involved in the initiation and progression of human malignancies by enabling cancer tissue self-renewal capacity and constituting the therapy-resistant population of tumor cells. However, despite the exhausting characterization of CSC genetics, epigenetics, and kinase signaling, eradication of CSCs remains an unattainable goal in most human malignancies. While phosphatases contribute equally with kinases to cellular phosphoregulation, our understanding of phosphatases in CSCs lags severely behind our knowledge about other CSC signaling mechanisms. Many cancer-relevant phosphatases have recently become druggable, indicating that further understanding of the CSC phosphatases might provide novel therapeutic opportunities. This review summarizes the current knowledge about fundamental, but yet poorly understood involvement of phosphatases in the regulation of major CSC signaling pathways. We also review the functional roles of phosphatases in CSC self-renewal, cancer progression, and therapy resistance; focusing particularly on hematological cancers and glioblastoma. We further discuss the small molecule targeting of CSC phosphatases and their therapeutic potential in cancer combination therapies.
Assuntos
Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Transdução de Sinais , Autorrenovação Celular/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética/genética , Humanos , Modelos Biológicos , Neoplasias/genética , Neoplasias/terapia , Células-Tronco Neoplásicas/enzimologia , Monoéster Fosfórico Hidrolases/classificaçãoRESUMO
We studied the transcriptive effects of two PAHs, retene (RET) and pyrene (PYR), in three equimolar sublethal concentrations (0.9-10 µg/L) in the liver of juvenile rainbow trout, Oncorhynchus mykiss. After 24 h of in vivo exposure, expressions of selected genes (CYP1A, Hsp30, Hsp70, Grp78, Sep15, GP1) were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). These PAHs changed the studied gene transcriptions differently, but not significantly, except for CYP1A, which was induced only by RET. RET induced CYP1A gene expression even at low, environmentally realistic concentrations in the liver of juvenile rainbow trout.
Assuntos
Proteínas de Peixes/genética , Fenantrenos/toxicidade , Pirenos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Monitoramento Ambiental , Proteínas de Peixes/metabolismo , Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Oncorhynchus mykissRESUMO
BACKGROUND: Mechanisms regulating the transition from hormone responsive to hormone refractory prostate cancer (PCa) have remained unclear. METHODS: We analyzed androgen and anti-androgen treatment on endogenous AR activity in primary human prostate epithelial (HPE) cells cultured directly from patient radical prostatectomy specimens utilizing a transiently infected gene reporter (TIGR) assay. RESULTS: Flutamide treatment exhibited agonist activities in HPE cells derived from tumor and non-tumor specimens which contained wild-type AR. After proteomic comparison of these cells to those where flutamide functioned normally as an antagonist, we identified DJ-1, a positive regulator of AR. DJ-1 expression increased in HPE and LNCaP cells during flutamide treatment as a result of DJ-1 protein stabilization. CONCLUSION: Stabilization of AR and its co-regulators in the absence of androgen may partially account for anti-androgen withdrawal syndrome and potentially contribute to the development of hormone refractory PCa.
