RESUMO
Most women diagnosed with high-grade serous ovarian cancer (HGSC) develop recurrent disease and chemotherapy resistance, despite initially responding to treatment. The genomic characteristics of HGSC samples collected at initial surgery have been extensively studied. However, due to challenges of sample collection following treatment, much less is known about the molecular features of recurrent disease. Our recent studies have identified mechanisms of acquired resistance and biomarkers in recurrent HGSCs that could lead to improved treatment approaches.
Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genéticaRESUMO
The Salvador-Warts-Hippo (SWH) pathway was first discovered in Drosophila melanogaster as a potent inhibitor of tissue growth. The SWH pathway is highly conserved between D. melanogaster and mammals, both in function and in the mechanism of signal transduction. The mammalian SWH pathway limits tissue growth by inhibiting the nuclear access and expression of the transcriptional co-activator, Yes-associated protein (YAP). Mutation and altered expression of SWH pathway proteins has been observed in several types of human cancer, but the contribution of these events to tumorigenesis has been unclear. Here we show that YAP can enhance the transformed phenotype of ovarian cancer cell lines and that YAP confers resistance to chemotherapeutic agents that are commonly used to treat ovarian cancer. We find that high nuclear YAP expression correlates with poor patient prognosis in a cohort of 268 invasive epithelial ovarian cancer samples. Segregation by histotype shows that the correlation between nuclear YAP and poor survival is predominantly associated with clear cell tumors, independent of stage. Collectively our findings suggest that YAP derepression contributes to the genesis of ovarian clear cell carcinoma and that the SWH pathway is an attractive therapeutic target.
Assuntos
Proteínas Nucleares/fisiologia , Oncogenes , Neoplasias Ovarianas/genética , Transativadores/fisiologia , Fatores de Transcrição/fisiologia , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Cisplatino/farmacologia , Feminino , Humanos , Proteínas Nucleares/genética , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Transativadores/genética , Fatores de Transcrição/genéticaRESUMO
Tumor hypoxia induces the upregulation of hypoxia-inducible factor 1alpha (Hif-1alpha), which in turn induces the expression of genes including VEGF to recruit new blood vessel outgrowth, enabling tumor growth and metastasis. Interference with the Hif-1 pathway and neoangiogenesis is an attractive antitumor target. The hydroxylation of Hif-1alpha by prolyl-hydroxylase (PHD) proteins during normoxia serves as a recognition motif for its proteasomal degradation. However, under hypoxic conditions, hydroxylation is inhibited and furthermore, PHD proteins are themselves polyubiquitylated and degraded by Siah ubiquitin ligases. Our data demonstrate for the first time that inhibition of the interaction between Siah and PHD proteins using a fragment derived from a Drosophila protein (phyllopod) interferes with the PHD degradation. Furthermore, cells stably expressing the phyllopod fragment display reduced upregulation of Hif-1alpha protein levels and Hif-1-mediated gene expression under hypoxia. In a syngeneic mouse model of breast cancer, the phyllopod fragment reduced tumor growth and neoangiogenesis and prolonged survival of the mice. In addition, levels of Hif-1alpha and its target Glut-1 are reduced in tumors expressing the phyllopod fragment. These data show, in a proof-of-principle study, that Siah protein, the most upstream component of the hypoxia pathway yet identified, is a viable drug target for antitumor therapies.
Assuntos
Proteínas de Drosophila/fisiologia , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/fisiologia , Fragmentos de Peptídeos/fisiologia , Proteínas/antagonistas & inibidores , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Hipóxia Celular/genética , Linhagem Celular Tumoral/metabolismo , Linhagem Celular Tumoral/transplante , Dioxigenases/metabolismo , Proteínas de Drosophila/genética , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/fisiologia , Neovascularização Patológica/enzimologia , Neovascularização Patológica/prevenção & controle , Proteínas Nucleares/genética , Fragmentos de Peptídeos/genética , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas/genética , Proteínas/fisiologia , Proteínas Recombinantes de Fusão/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Ubiquitinação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Retinoids induce growth arrest, differentiation, and cell death in many cancer cell types. One factor determining the sensitivity or resistance to the retinoid anticancer signal is the transcriptional response of retinoid-regulated target genes in cancer cells. We used cDNA microarray to identify 31 retinoid-regulated target genes shared by two retinoid-sensitive neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the retinoid anticancer signal. The pattern of retinoid responsiveness for six of 13 target genes (RARbeta2, CYP26A1, CRBP1, RGS16, DUSP6, EGR1) correlated with phenotypic retinoid sensitivity, across a panel of retinoid-sensitive or -resistant lung and breast cancer cell lines. Retinoid treatment of MYCN transgenic mice bearing neuroblastoma altered the expression of five of nine target genes examined (RARbeta2, CYP26A1, CRBP1, DUSP6, PLAT) in neuroblastoma tumour tissue in vivo. In retinoid-sensitive neuroblastoma, lung and breast cancer cell lines, direct inhibition of retinoid-induced RARbeta2 expression blocked induction of only one of eight retinoid target genes (CYP26A1). DNA demethylation, histone acetylation, and exogenous overexpression of RARbeta2 partially restored retinoid-responsive CYP26A1 expression in RA-resistant MDA-MB-231 breast, but not SK-MES-1 lung, cancer cells. Combined, rather than individual, inhibition of DUSP6 and RGS16 was required to block retinoid-induced growth inhibition in neuroblastoma cells, through phosphorylation of extracellular-signal-regulated kinase. In conclusion, sensitivity to the retinoid anticancer signal is determined in part by the transcriptional response of key retinoid-regulated target genes, such as RARbeta2, DUSP6, and RGS16.