RESUMEN
According to epidemiological research, skin autoimmune diseases are more prevalent among black Americans. We postulated that pigment-producing melanocytes may contribute to local immune regulation in the microenvironment. We examined murine epidermal melanocytes in vitro to determine the role of pigment production in immune responses mediated by dendritic cell (DC) activation. Our study revealed that darkly pigmented melanocytes produce more IL-3 and the pro-inflammatory cytokines, IL-6 and TNF-α, and consequently induce plasmacytoid DC (pDC) maturation. Additionally, we demonstrate that low pigment-associated fibromodulin (FMOD) interferes with cytokine secretion and subsequent pDC maturation.
Asunto(s)
Citocinas , Interleucina-3 , Humanos , Animales , Ratones , Interleucina-3/metabolismo , Interleucina-3/farmacología , Fibromodulina/metabolismo , Citocinas/metabolismo , Pigmentación , Células DendríticasRESUMEN
Skin pigmentation has been linked to the development, prevalence, and severity of several immune-mediated diseases such as SLE. Here, we asked whether fibromodulin (FMOD), which is highly expressed in skin with light complexion, can explain the known differences in the magnitude of inflammation. C57 mice with different levels of pigmentation and FMOD were injected with human lupus serum to induce skin inflammation. Histopathologic studies revealed that black C57 FMOD+/+ that produce low levels of FMOD and white C57 FMOD -/- mice develop more severe inflammation compared with white FMOD +/+ mice. This study also revealed that dark pigmentation and FMOD deletion correlates with the increased numbers of Langerhans cells. Altogether, we identify low pigmentation and FMOD are linked to low severity of inflammation and approaches to promote FMOD expression should offer clinical benefit.
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Fibromodulina , Inflamación , Melanocitos , Piel , Animales , Fibromodulina/metabolismo , Humanos , Inflamación/metabolismo , Lupus Eritematoso Sistémico , Ratones , Piel/metabolismo , Piel/patología , Pigmentación de la PielRESUMEN
The oncogenic transcription factor FOXM1 is overexpressed in the majority of human cancers, and it is a potential target for anticancer therapy. We identified proteasome inhibitors as the first type of drugs that target FOXM1 in cancer cells. Here we found that HSP90 inhibitor PF-4942847 and heat shock also suppress FOXM1. The common effector, which was induced after treatment with proteasome and HSP90 inhibitors or heat shock, was the molecular chaperone HSP70. We show that HSP70 binds to FOXM1 following proteotoxic stress and that HSP70 inhibits FOXM1 DNA-binding ability. Inhibition of FOXM1 transcriptional autoregulation by HSP70 leads to the suppression of FOXM1 protein expression. In addition, HSP70 suppression elevates FOXM1 expression, and simultaneous inhibition of FOXM1 and HSP70 increases the sensitivity of human cancer cells to anticancer drug-induced apoptosis. Overall, we determined the unique and novel mechanism of FOXM1 suppression by proteasome inhibitors.
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Factores de Transcripción Forkhead/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Inhibidores de Proteasoma/farmacología , Estrés Fisiológico/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , ADN/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Proteína Forkhead Box M1 , Humanos , Modelos Biológicos , Unión Proteica/efectos de los fármacos , Secuencias Reguladoras de Ácidos Nucleicos/genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Tumor cells accumulate high level of reactive oxygen species (ROS) because they are metabolically more active than normal cells. Elevated ROS levels increase tumorigenecity but also render cancer cells more vulnerable to oxidative stress than normal cells. The oncogenic transcription factor Forkhead Box M1 (FOXM1), which is overexpressed in a wide range of human cancers, was reported to protect cancer cells from the adverse effects of oxidative stress by up regulating the expression of scavenger enzymes. We therefore hypothesized that the combination of FOXM1 ablation and ROS inducers could selectively eradicate cancer cells. We show that RNA interference-mediated knockdown of FOXM1 further elevates intracellular ROS levels and increases sensitivity of cancer cells to ROS-mediated cell death after treatment with ROS inducers. We also demonstrate that the combination of ROS inducers with FOXM1/proteasome inhibitors induces robust apoptosis in different human cancer cells. In addition, we show evidence that FOXM1/proteasome inhibitor bortezomib in combination with the ROS inducer ß-phenylethyl isothiocyanate efficiently inhibits the growth of breast tumor xenografts in nude mice. We conclude that the combination of ROS inducers and FOXM1 inhibitors could be used as a therapeutic strategy to selectively eliminate cancer cells.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/antagonistas & inhibidores , Factores de Transcripción Forkhead/antagonistas & inhibidores , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , 2-Metoxiestradiol , Animales , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Ácidos Borónicos/administración & dosificación , Bortezomib , Línea Celular Tumoral , Esquema de Medicación , Estradiol/administración & dosificación , Estradiol/análogos & derivados , Femenino , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Humanos , Isotiocianatos/administración & dosificación , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Desnudos , Pirazinas/administración & dosificación , Interferencia de ARN , Distribución Aleatoria , Especies Reactivas de Oxígeno/metabolismo , Trasplante Heterólogo , Resultado del TratamientoRESUMEN
NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H2O2. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.
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Acetilcisteína/farmacología , Depuradores de Radicales Libres/farmacología , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Inhibidores de Proteasoma/farmacología , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Acetilcisteína/metabolismo , Antineoplásicos Fitogénicos/antagonistas & inhibidores , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Catalasa/genética , Catalasa/metabolismo , Línea Celular Tumoral , Cromanos/antagonistas & inhibidores , Cromanos/metabolismo , Cromanos/farmacología , Citomegalovirus/enzimología , Dioxolanos/antagonistas & inhibidores , Dioxolanos/farmacología , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/antagonistas & inhibidores , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Depuradores de Radicales Libres/metabolismo , Humanos , Peróxido de Hidrógeno/antagonistas & inhibidores , Peróxido de Hidrógeno/farmacología , Oxidantes/antagonistas & inhibidores , Oxidantes/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/metabolismo , Estabilidad Proteica/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Proteínas Ubiquitinadas/metabolismo , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
Using mass spectrometric analysis we found that oncogenic transcription factor FOXM1 that is overexpressed in a majority of human cancers interacts with multifunctional protein NPM, which is also overexpressed in a variety of human tumors. Coimmunoprecipitation and glutathione S-transferase pull-down experiments demonstrated that NPM forms a complex with FOXM1 and also identified the regions responsible for their interaction. Immunofluorescence microscopy confirmed the interaction between FOXM1 and NPM in cancer and immortal cells. Furthermore, knockdown of NPM in immortal and cancer cells led to significant down-regulation of FOXM1 similar to its levels in normal cells, suggesting that NPM might modulate FOXM1 level. In addition, in OCI/AML3 leukemia cells where mutant NPM is localized in the cytoplasm we found that typically nuclear FOXM1 was predominantly co-localized with NPM in the cytoplasm, while NPM knockdown led to the disappearance of FOXM1 from the cytoplasm, suggesting that NPM may also determine intracellular localization of FOXM1. Knockdown of FOXM1 or NPM in MIA PaCa-2 pancreatic cancer cells inhibited anchorage-dependent and independent growth in cell culture, and tumor growth in nude mice. In addition, over-expression of FOXM1 reversed the effect of NPM knockdown in vitro. Our data suggest that in cancer cells NPM interacts with FOXM1 and their interaction is required for sustaining the level and localization of FOXM1. Targeting the interaction between FOXM1 and NPM by peptides or small molecules may represent a novel therapeutic strategy against cancer.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Animales , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/genética , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Masculino , Ratones , Ratones Desnudos , Mutación , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/terapia , Proteínas Nucleares/genética , Nucleofosmina , Transporte de Proteínas/genéticaRESUMEN
Introduction: Epidemiological studies have associated pigment production with protection against certain human diseases. In contrast to African Americans, European descendants are more likely to suffer from angiogenesis-dependent and inflammatory diseases, such as wet age-related macular degeneration (ARMD) and ulcerative colitis (UC), respectively. Methods: In a mouse model of dextran sulfate sodium (DSS)-induced acute colitis, the effect of fibromodulin (FMOD) depletion was examined on colitis severity. Results: In this study, albino mice that produce high levels of FMOD developed less severe acute colitis compared with mice lacking in FMOD as assessed by clinical symptoms and histopathological changes. FMOD depletion affected the expression of tight junction proteins, contributing to the destruction of the epithelial barrier. Furthermore, this study revealed a stronger inflammatory response after DSS treatment in the absence of FMOD, where FMOD depletion led to an increase in activated T cells, plasmacytoid dendritic cells (pDCs), and type I interferon (IFN) production. Discussion: These findings point to FMOD as a potential biomarker of disease severity in UC among light-skinned individuals of European descent.
RESUMEN
Several angiogenesis-dependent diseases, including age-related macular degeneration and infantile hemangioma, display differential prevalence among Black, as compared to White individuals. Although socioeconomic status and genetic architecture have been suggested as explaining these differences, we have recently shown that pigment production per se might be involved. For example, we have shown that the extracellular protein fibromodulin is a pro-angiogenic factor highly secreted by melanocytes in White but not Black individuals. Still, additional pigment-dependent angiogenic factors and their molecular mechanisms remain to be identified. Understanding the contribution of pigmentation to angiogenesis in health and disease is essential for precision medicine of angiogenesis-dependent diseases with racial disparity. Toward that goal, we compared the transcriptomes of Black and White individuals in three tissues with angiogenic activity, namely artery, whole blood, and skin. We identified several differentially expressed angiogenesis pathways, including artery morphogenesis, regulation of endothelial cell chemotaxis, and cellular response to vascular endothelial growth factor stimulus. We then demonstrated that the expression of key genes in these pathways is directly modulated by the degree of pigmentation. We further identified the precise pigment production pathway controlling the expression of these genes, namely melanocortin 1 receptor (MC1R) signaling. These results demonstrate pigment-mediated regulation of angiogenesis-related pathways and their driver genes across human tissues.
Asunto(s)
Melanocitos/metabolismo , Neovascularización Fisiológica/genética , Neovascularización Fisiológica/fisiología , Animales , Arterias/metabolismo , Población Negra/genética , Sangre/metabolismo , Bases de Datos Genéticas , Femenino , Expresión Génica/genética , Regulación de la Expresión Génica/genética , Humanos , Masculino , Melanocitos/fisiología , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica/inmunología , Especificidad de Órganos/genética , Receptor de Melanocortina Tipo 1/genética , Receptor de Melanocortina Tipo 1/metabolismo , Piel/metabolismo , Transcriptoma/genética , Población Blanca/genéticaRESUMEN
Forkhead box protein M1 (FOXM1) is a crucial regulator of cancer development and chemoresistance. It is often overexpressed in acute myeloid leukemia (AML) and is associated with poor survival and reduced efficacy of cytarabine therapy. Molecular mechanisms underlying high FOXM1 expression levels in malignant cells are still unclear. Here we demonstrate that AKT and FOXM1 constitute a positive autoregulatory loop in AML cells that sustains high activity of both pro-oncogenic regulators. Inactivation of either AKT or FOXM1 signaling results in disruption of whole loop, coordinated suppression of FOXM1 or AKT, respectively, and similar transcriptomic changes. AML cells with inhibited AKT activity or stable FOXM1 knockdown display increase in HOXA genes expression and BCL2L1 suppression that are associated with prominent sensitization to treatment with Bcl-2 inhibitor venetoclax. Taken together, our data indicate that AKT and FOXM1 in AML cells should not be evaluated as single independent regulators but as two parts of a common FOXM1-AKT positive feedback circuit. We also report for the first time that FOXM1 inactivation can overcome AML venetoclax resistance. Thus, targeting FOXM1-AKT loop may open new possibilities in overcoming AML drug resistance and improving outcomes for AML patients.
RESUMEN
FOXM1 transcription factor is an oncogene and a master regulator of chemoresistance in multiple cancers. Pharmacological inhibition of FOXM1 is a promising approach but has proven to be challenging. We performed a network-centric transcriptomic analysis to identify a novel compound STL427944 that selectively suppresses FOXM1 by inducing the relocalization of nuclear FOXM1 protein to the cytoplasm and promoting its subsequent degradation by autophagosomes. Human cancer cells treated with STL427944 exhibit increased sensitivity to cytotoxic effects of conventional chemotherapeutic treatments (platinum-based agents, 5-fluorouracil, and taxanes). RNA-seq analysis of STL427944-induced gene expression changes revealed prominent suppression of gene signatures characteristic for FOXM1 and its downstream targets but no significant changes in other important regulatory pathways, thereby suggesting high selectivity of STL427944 toward the FOXM1 pathway. Collectively, the novel autophagy-dependent mode of FOXM1 suppression by STL427944 validates a unique pathway to overcome tumor chemoresistance and improve the efficacy of treatment with conventional cancer drugs.
Asunto(s)
Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Proteína Forkhead Box M1/antagonistas & inhibidores , Perfilación de la Expresión Génica , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Estabilidad Proteica , Transporte de Proteínas , Proteolisis , RNA-Seq , TranscriptomaRESUMEN
Honokiol is a natural product and an emerging drug for a wide variety of malignancies, including hematopoietic malignancies, sarcomas, and common epithelial tumors. The broad range of activity of honokiol against numerous malignancies with diverse genetic backgrounds suggests that honokiol is inhibiting an activity that is common to multiple malignancies. Oncogenic transcription factor FOXM1 is one of the most overexpressed oncoproteins in human cancer. Here we found that honokiol inhibits FOXM1-mediated transcription and FOXM1 protein expression. More importantly, we found that honokiol's inhibitory effect on FOXM1 is a result of binding of honokiol to FOXM1. This binding is specific to honokiol, a dimerized allylphenol, and was not observed in compounds that either were monomeric allylphenols or un-substituted dihydroxy phenols. This indicates that both substitution and dimerization of allylphenols are required for physical interaction with FOXM1. We thus demonstrate a novel and specific mechanism for FOXM1 inhibition by honokiol, which partially may explain its anticancer activity in cancer cells.
Asunto(s)
Compuestos de Bifenilo/farmacología , Proteína Forkhead Box M1/antagonistas & inhibidores , Lignanos/farmacología , Animales , Compuestos de Bifenilo/química , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Humanos , Lignanos/química , Ratones , Inhibidores de Proteasoma/farmacología , Activación Transcripcional/efectos de los fármacosRESUMEN
Acute myeloid leukemia (AML) patients with NPM1 mutations demonstrate a superior response to standard chemotherapy treatment. Our previous work has shown that these favorable outcomes are linked to the cytoplasmic relocalization and inactivation of FOXM1 driven by mutated NPM1. Here, we went on to confirm the important role of FOXM1 in increased chemoresistance in AML. A multiinstitution retrospective study was conducted to link FOXM1 expression to clinical outcomes in AML. We establish nuclear FOXM1 as an independent clinical predictor of chemotherapeutic resistance in intermediate-risk AML in a multivariate analysis incorporating standard clinicopathologic risk factors. Using colony assays, we show a dramatic decrease in colony size and numbers in AML cell lines with knockdown of FOXM1, suggesting an important role for FOXM1 in the clonogenic activity of AML cells. In order to further prove a potential role for FOXM1 in AML chemoresistance, we induced an FLT3-ITD-driven myeloid neoplasm in a FOXM1-overexpressing transgenic mouse model and demonstrated significantly higher residual disease after standard chemotherapy. This suggests that constitutive overexpression of FOXM1 in this model induces chemoresistance. Finally, we performed proof-of-principle experiments using a currently approved proteasome inhibitor, ixazomib, to target FOXM1 and demonstrated a therapeutic response in AML patient samples and animal models of AML that correlates with the suppression of FOXM1 and its transcriptional targets. Addition of low doses of ixazomib increases sensitization of AML cells to chemotherapy backbone drugs cytarabine and the hypomethylator 5-azacitidine. Our results underscore the importance of FOXM1 in AML progression and treatment, and they suggest that targeting it may have therapeutic benefit in combination with standard AML therapies.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos/genética , Proteína Forkhead Box M1/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteasoma/farmacología , Anciano , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos de Boro/farmacología , Compuestos de Boro/uso terapéutico , Línea Celular Tumoral , Núcleo Celular/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Proteína Forkhead Box M1/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Glicina/análogos & derivados , Glicina/farmacología , Glicina/uso terapéutico , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Ratones , Persona de Mediana Edad , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Cultivo Primario de Células , Inhibidores de Proteasoma/uso terapéutico , Estudios Retrospectivos , Insuficiencia del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Tumor suppressor p53 is one of the most frequently mutated genes in cancer, with almost 50% of all types of cancer expressing a mutant form of p53. p53 transactivates the expression of its primary negative regulator, HDM2. HDM2 is a ubiquitin ligase, which initiates the proteasomal degradation of p53 following ubiquitination. Proteasome inhibitors, by targeting the ubiquitin proteasome pathway inhibit the degradation of the majority of cellular proteins including wild-type p53. In contrast, in this study we found that the protein expression of mutant p53 was suppressed following treatment with established or novel proteasome inhibitors. Furthermore, for the first time we demonstrated that Arsenic trioxide, which was previously shown to suppress mutant p53 protein level, exhibits proteasome inhibitory activity. Proteasome inhibitor-mediated suppression of mutant p53 was partially rescued by the knockdown of HDM2, suggesting that the stabilization of HDM2 by proteasome inhibitors might be responsible for mutant p53 suppression to some extent. This study suggests that suppression of mutant p53 is a general property of proteasome inhibitors and it provides additional rationale to use proteasome inhibitors for the treatment of tumors with mutant p53.
Asunto(s)
Inhibidores de Proteasoma/farmacología , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Trióxido de Arsénico , Arsenicales/farmacología , Línea Celular Tumoral , Humanos , Óxidos/farmacología , Proteínas Proto-Oncogénicas c-mdm2/genética , Interferencia de ARN , Proteína p53 Supresora de Tumor/genéticaRESUMEN
FOXM1 is an oncogenic transcription factor of the Forkhead family and it has a well-defined role in cell proliferation and cell-cycle progression. Expression of FOXM1 is excluded in quiescent or differentiated cells, but its level is highly elevated in proliferating and malignant cells. Overexpression of FOXM1 has been reported in more than 20 types of human cancer. In recent years, FOXM1 has been implicated in diverse cellular processes and also a growing body of experimental data has underlined the relevance of FOXM1 in tumorigenesis. Although FOXM1 is under the control of three major tumor suppressors (RB, p53, and p19(ARF)), it is still active in the majority of human cancers. The oncogenic potential of FOXM1 is mainly based on its ability to transcriptionally activate genes that are involved in different facets of cancer development. In this review, the contribution of FOXM1 to each of the hallmarks of cancer will be summarized and discussed.
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Transformación Celular Neoplásica/genética , Factores de Transcripción Forkhead/genética , Neoplasias/genética , Activación Transcripcional/genética , Puntos de Control del Ciclo Celular , Proliferación Celular , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , HumanosRESUMEN
Oncogenic transcription factor FOXM1 is overexpressed in the majority of human cancers. In addition, FOXM1 has been implicated in cell migration, invasion, angiogenesis and metastasis. The important role of FOXM1 in cancer affirms its significance for therapeutic intervention. Current data suggest that targeting FOXM1 in mono- or combination therapy may have promising therapeutic benefits for the treatment of cancer. However, challenges with the delivery of anti-FOXM1 siRNA to tumors and the absence of small molecules, which specifically inhibit FOXM1, are delaying the development of FOXM1 inhibitors as feasible anticancer drugs. In this review, we describe and summarize the efforts that have been made to target FOXM1 in cancer and the consequences of FOXM1 suppression in human cancer cells.
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Antineoplásicos/uso terapéutico , Factores de Transcripción Forkhead/antagonistas & inhibidores , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Neoplasias/terapia , Antineoplásicos/química , Antineoplásicos/clasificación , Diseño de Fármacos , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/genética , Humanos , Neoplasias/metabolismo , Interferencia de ARNRESUMEN
Irradiation and DNA-damaging chemotherapeutic agents are commonly used in anticancer treatments. Following DNA damage FOXM1 protein levels are often elevated. In this study, we sought to investigate the potential role of FOXM1 in programmed cell death induced by DNA-damage. Human cancer cells after FOXM1 suppression were subjected to doxorubicin or γ-irradiation treatment. Our findings indicate that FOXM1 downregulation by stable or transient knockdown using RNAi or by treatment with proteasome inhibitors that target FOXM1 strongly sensitized human cancer cells of different origin to DNA-damage-induced apoptosis. We showed that FOXM1 suppresses the activation of pro-apoptotic JNK and positively regulates anti-apoptotic Bcl-2, suggesting that JNK activation and Bcl-2 down-regulation could mediate sensitivity to DNA-damaging agent-induced apoptosis after targeting FOXM1. Since FOXM1 is widely expressed in human cancers, our data further support the fact that it is a valid target for combinatorial anticancer therapy.
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Apoptosis , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica , Antineoplásicos/farmacología , Muerte Celular , Línea Celular Tumoral , Daño del ADN , Relación Dosis-Respuesta en la Radiación , Regulación hacia Abajo , Proteína Forkhead Box M1 , Humanos , MAP Quinasa Quinasa 4/metabolismo , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasoma , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Células MadreRESUMEN
Nanoparticle-encapsulated thiazole antibiotic, thiostrepton, has been shown to be an effective agent for inhibiting tumor growth in solid tumor models through the inhibition of proteasomal activity by the induction of apoptosis in cancer cells. Here, we show the efficacy of thiostrepton-micelles in inhibiting tumor growth in a DEN/PB-induced liver cancer model. We also demonstrate an enhanced anticancer effect of the combination treatment of thiostrepton with bortezomib, another proteasome inhibitor in this liver cancer model.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácidos Borónicos/uso terapéutico , Transformación Celular Neoplásica/patología , Neoplasias Hepáticas/tratamiento farmacológico , Pirazinas/uso terapéutico , Tioestreptona/uso terapéutico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ácidos Borónicos/farmacología , Bortezomib , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Transformación Celular Neoplásica/efectos de los fármacos , Dietilnitrosamina , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/patología , Neoplasias Hepáticas/patología , Ratones , Fenobarbital , Pirazinas/farmacología , Tioestreptona/farmacologíaRESUMEN
Oncogenic transcription factor FoxM1 represents an attractive therapeutic target in the fight against cancer, because it is overexpressed in a majority of human tumors. Previously, we identified the thiazole antibiotics as potent inhibitors of FoxM1. Surprisingly, investigation of the mechanism of action of FoxM1 inhibitors revealed a novel mode of positive auto-regulation of FoxM1.
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Retroalimentación Fisiológica , Factores de Transcripción Forkhead/metabolismo , Línea Celular Tumoral , Proteína Forkhead Box M1 , Factores de Transcripción Forkhead/antagonistas & inhibidores , Factores de Transcripción Forkhead/genética , Humanos , Péptidos/farmacología , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/biosíntesis , Proteínas Recombinantes de Fusión/metabolismo , Tioestreptona/farmacologíaRESUMEN
The Forkhead box M1 (FoxM1) oncogenic transcription factor is overexpressed in a majority of human tumors. p53 is a transcription factor and a major tumor suppressor that is mutated in 50% of human cancers. In this study, we compared the levels of FoxM1 in normal BJ human fibroblasts, BJ fibroblasts with p53 knockdown and corresponding BJ immortal/oncogenic cell lines with inactivated p53. We found that partial deletion or inactivation of p53 in these cells leads to upregulation of FoxM1 expression. Similarly, p53 knockdown in several human cancer cell lines with wt-p53 led to upregulation of FoxM1 mRNA and protein expression, while induction of p53 by DNA-damage led to downregulation of FoxM1. These data suggest that p53 negatively regulates FoxM1 expression and therefore inactivation of p53 in tumors could partially explain the phenomenon of FoxM1 overexpression in human cancers.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Proteína p53 Supresora de Tumor/fisiología , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Daño del ADN , Proteína Forkhead Box M1 , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , ARN Interferente Pequeño/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba , Quinasa Tipo Polo 1RESUMEN
Forkhead box M1 (FoxM1) oncogenic transcription factor represents an attractive therapeutic target in the fight against cancer, because it is overexpressed in a majority of human tumors. Recently, using a cell-based assay system we identified thiazole antibiotic Siomycin A as an inhibitor of FoxM1 transcriptional activity. Here, we report that structurally similar thiazole antibiotic, thiostrepton also inhibits the transcriptional activity of FoxM1. Furthermore, we found that these thiopeptides did not inhibit the transcriptional activity of other members of the Forkhead family or some non-related transcription factors. Further experiments revealed that thiazole antibiotics also inhibit FoxM1 expression, but not the expression of other members of the Forkhead box family. In addition, we found that the thiazole antibiotics efficiently inhibited the growth and induced potent apoptosis in human cancer cell lines of different origin. Thiopeptide-induced apoptosis correlated with the suppression of FoxM1 expression, while overexpression of FoxM1 partially protected cancer cells from the thiazole antibiotic-mediated cell death. These data suggest that Siomycin A and thiostrepton may specifically target FoxM1 to induce apoptosis in cancer cells and FoxM1 inhibitors/thiazole antibiotics could be potentially developed as novel anticancer drugs against human neoplasia.