RESUMO
The efficacy of ionizing radiation (IR) for head and neck cancer squamous cell carcinoma (HNSCC) is limited by poorly understood mechanisms of adaptive radioresistance. Elevated glutaminase gene expression is linked to significantly reduced survival (p < 0.03). The glutaminase inhibitor, telaglenastat (CB-839), has been tested in Phase I/II cancer trials and is well tolerated by patients. This study investigated if telaglenastat enhances the cellular response to IR in HNSCC models. Using three human HNSCC cell lines and two xenograft mouse models, we examined telaglenastat's effects on radiation sensitivity. IR and telaglenastat combinatorial treatment reduced cell survival (p ≤ 0.05), spheroid size (p ≤ 0.0001) and tumor growth in CAL-27 xenograft bearing mice relative to vehicle (p ≤ 0.01), telaglenastat (p ≤ 0.05) or IR (p ≤ 0.01) monotherapy. Telaglenastat significantly reduced the Oxygen Consumption Rate/Extracellular Acidification Rate ratio in CAL-27 and HN5 cells in the presence of glucose and glutamine (p ≤ 0.0001). Telaglenastat increased oxidative stress and DNA damage in irradiated CAL-27 cells. These data suggest that combination treatment with IR and telaglenastat leads to an enhanced anti-tumor response. This pre-clinical data, combined with the established safety of telaglenastat justifies further investigation for the combination in HNSCC patients.
Assuntos
Benzenoacetamidas/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Neoplasias de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Tiadiazóis/administração & dosagem , Animais , Benzenoacetamidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quimiorradioterapia , Inibidores Enzimáticos/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Camundongos , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/efeitos da radiação , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Tiadiazóis/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Metal nanoparticles have significant interaction cross-sections with electromagnetic waves due to their large surface area-to-volume ratio, which can be exploited in cancer radiotherapy to locally enhance the radiation dose deposition in tumors. We developed a new type of silver nanoparticle composite, PEGylated graphene quantum dot (GQD)-decorated Silver Nanoprisms (pGAgNPs), that show excellent in vitro intracellular uptake and radiosensitization in radiation-sensitive HCT116 and relatively radiation-resistant HT29 colorectal cancer cells. Furthermore, following biodistribution analysis of intravenously injected nanoparticles in nude mice bearing HCT116 tumors radiosensitization was evaluated. Treatment with nanoparticles and a single radiation dose of 10 Gy significantly reduces the growth of colorectal tumors and increases the survival time as compared to treatment with radiation only. Our findings suggest that these novel nanoparticles offer a promising paradigm for enhancing colorectal cancer radiation therapy efficacy.
Assuntos
Neoplasias Colorretais/radioterapia , Grafite/química , Nanopartículas Metálicas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Prata/química , Animais , Apoptose , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Raios gama , Humanos , Masculino , Nanopartículas Metálicas/química , Camundongos , Pontos Quânticos , Radiossensibilizantes/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Radiotherapy is a component of the standard of care for many patients with locally advanced nonmetastatic tumors and increasingly those with oligometastatic tumors. Despite encouraging advances in local control and progression-free and overall survival outcomes, continued manifestation of tumor progression or recurrence leaves room for improvement in therapeutic efficacy. Novel combinations of radiation with immunotherapy have shown promise in improving outcomes and reducing recurrences by overcoming tumor immune tolerance and evasion mechanisms via boosting the immune system's ability to recognize and eradicate tumor cells. In this review, we discuss preclinical and early clinical evidence that radiotherapy and immunotherapy can improve treatment outcomes for locally advanced and metastatic tumors, elucidate underlying molecular mechanisms and address strategies to optimize timing and sequencing of combination therapy for maximal synergy.
Assuntos
Imunoterapia/métodos , Neoplasias/terapia , Animais , Protocolos Clínicos , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias/imunologia , Neoplasias/radioterapiaRESUMO
Theoretical investigations suggest that gold nanoparticle (GNP)-mediated radiation dose enhancement and radiosensitization can be maximized when photons interact with gold, predominantly via photoelectric absorption. This makes ytterbium (Yb)-169, which emits photons with an average energy of 93 keV (just above the K-edge of gold), an ideal radioisotope for such purposes. This investigation tests the feasibility of tumor-specific prostate brachytherapy achievable with Yb-169 and actively targeted GNPs, using an external beam surrogate of Yb-169 created from an exotic filter material - erbium (Er) and a standard copper-filtered 250 kVp beam. The current in vitro study shows that treatment of prostate cancer cells with goserelin-conjugated gold nanorods (gGNRs) promotes gonadotropin releasing hormone receptor-mediated internalization and enhances radiosensitivity to both Er-filtered and standard 250 kVp beams, 14 and 10%, respectively. While the degree of GNP-mediated radiosensitization as seen from the in vitro study may be considered moderate, the current in vivo study shows that gGNR treatment plus Er-filtered x-ray irradiation is considerably more effective than radiation treatment alone (p < 0.0005), resulting in a striking reduction in tumor volume (50% smaller) 2 months following treatment. Overall, the current results provide strong evidence for the feasibility of tumor-specific prostate brachytherapy with Yb-169 and gGNRs.
Assuntos
Braquiterapia/métodos , Ouro/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Próstata/efeitos da radiação , Neoplasias da Próstata/radioterapia , Radiossensibilizantes/uso terapêutico , Animais , Érbio , Ouro/administração & dosagem , Humanos , Masculino , Nanopartículas Metálicas/administração & dosagem , Camundongos , Camundongos Nus , Células PC-3 , Próstata/patologia , Neoplasias da Próstata/patologia , Radiossensibilizantes/administração & dosagem , Raios XRESUMO
Protein tyrosine phosphorylation, which plays a vital role in a variety of human cellular processes, is coordinated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Genomic studies provide compelling evidence that PTPs are frequently mutated in various human cancers, suggesting that they have important roles in tumor suppression. However, the cellular functions and regulatory machineries of most PTPs are still largely unknown. To gain a comprehensive understanding of the protein-protein interaction network of the human PTP family, we performed a global proteomic study. Using a Minkowski distance-based unified scoring environment (MUSE) for the data analysis, we identified 940 high confidence candidate-interacting proteins that comprise the interaction landscape of the human PTP family. Through a gene ontology analysis and functional validations, we connected the PTP family with several key signaling pathways or cellular functions whose associations were previously unclear, such as the RAS-RAF-MEK pathway, the Hippo-YAP pathway, and cytokinesis. Our study provides the first glimpse of a protein interaction network for the human PTP family, linking it to a number of crucial signaling events, and generating a useful resource for future studies of PTPs.
Assuntos
Mapas de Interação de Proteínas , Proteínas Tirosina Fosfatases/metabolismo , Proteômica/métodos , Ontologia Genética , Redes Reguladoras de Genes , Células HEK293 , Células HeLa , Humanos , Família Multigênica , Especificidade por SubstratoRESUMO
By combining the results of a large-scale proteomic analysis of the human transcription factor interaction network with knowledge databases, we identified FOXR2 as one of the top-ranked candidate proto-oncogenes. Here, we show that FOXR2 forms a stable complex with MYC and MAX and subsequently regulates cell proliferation by promoting MYC's transcriptional activities. We demonstrate that FOXR2 is highly expressed in several breast, lung, and liver cancer cell lines and related patient tumor samples, while reduction of FOXR2 expression in a xenograft model inhibits tumor growth. These results indicate that FOXR2 acts with MYC to promote cancer cell proliferation, which is a potential tumor-specific target for therapeutic intervention against MYC-driven cancers.
Assuntos
Neoplasias da Mama/metabolismo , Carcinogênese/metabolismo , Fatores de Transcrição Forkhead/fisiologia , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-myc/fisiologia , Ativação Transcricional , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Fatores de Transcrição Forkhead/química , Expressão Gênica , Células HEK293 , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Domínios e Motivos de Interação entre Proteínas , Mapas de Interação de Proteínas , Multimerização Proteica , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-myc/químicaRESUMO
The protein tyrosine phosphatase receptor PTPRN2 is expressed predominantly in endocrine and neuronal cells, where it functions in exocytosis. We found that its immature isoform proPTPRN2 is overexpressed in various cancers, including breast cancer. High proPTPRN2 expression was associated strongly with lymph node-positive breast cancer and poor clinical outcome. Loss of proPTPRN2 in breast cancer cells promoted apoptosis and blocked tumor formation in mice, whereas enforced expression of proPTPRN2 in nontransformed human mammary epithelial cells exerted a converse effect. Mechanistic investigations suggested that ProPTPRN2 elicited these effects through direct interaction with TRAF2, a hub scaffold protein for multiple kinase cascades, including ones that activate NF-κB. Overall, our results suggest PTPRN2 as a novel candidate biomarker and therapeutic target in breast cancer.
Assuntos
Apoptose/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/biossíntese , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Células HCT116 , Células HEK293 , Células HeLa , Xenoenxertos , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Células MCF-7 , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/genética , NF-kappa B/metabolismo , Neoplasias/genética , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/metabolismoRESUMO
Dishevelled (DVL) proteins serve as crucial regulators that transduce canonical Wnt signals to the GSK3ß-destruction complex, resulting in the stabilization of ß-catenin. Emerging evidence underscores the nuclear functions of DVLs, which are critical for Wnt/ß-catenin signaling. However, the mechanism underlying DVL nuclear localization remains poorly understood. Here we discovered two Forkhead box (FOX) transcription factors, FOXK1 and FOXK2, as bona fide DVL-interacting proteins. FOXK1 and FOXK2 positively regulate Wnt/ß-catenin signaling by translocating DVL into the nucleus. Moreover, FOXK1 and FOXK2 protein levels are elevated in human colorectal cancers and correlate with DVL nuclear localization. Conditional expression of Foxk2 in mice induced intestinal hyper-proliferation that featured enhanced DVL nuclear localization and upregulated Wnt/ß-catenin signaling. Together, our results not only reveal a mechanism by which DVL is translocated into the nucleus but also suggest unexpected roles of FOXK1 and FOXK2 in regulating Wnt/ß-catenin signaling.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Fosfoproteínas/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Sítios de Ligação/genética , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Neoplasias Colorretais/metabolismo , Proteínas Desgrenhadas , Feminino , Fatores de Transcrição Forkhead/biossíntese , Células HEK293 , Células HT29 , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Transplante de Neoplasias , Ligação Proteica , Ativação Transcricional , Transplante Heterólogo , Via de Sinalização WntRESUMO
The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source used for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 (GLUT3) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention.