RESUMEN
The transcriptional co-activators Yes-associated protein (YAP) and PDZ-binding domain (TAZ) are the known downstream effectors of the Hippo kinase cascade. YAP/TAZ have been shown to play important roles in cellular growth and differentiation, tissue development and carcinogenesis. Recent studies have found that, in addition to the Hippo kinase cascade, multiple non-Hippo kinases also regulate the YAP/TAZ cellular signaling and produce important effects on cellular functions, particularly on tumorigenesis and progression. In this article, we will review the multifaceted regulation of the YAP/TAZ signaling by the non-Hippo kinases and discuss the potential application of the non-Hippo kinase-regulated YAP/TAZ signaling for cancer therapy.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas Serina-Treonina Quinasas , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Transactivadores/metabolismo , Proteínas Señalizadoras YAP , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Vía de Señalización Hippo , Fosfoproteínas/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , CarcinogénesisRESUMEN
The Hippo pathway is an evolutionarily conserved signaling pathway that plays critical roles in the tumorigenesis and progression of breast cancer, oral cancer, rectal cancer, colloid cancer, and so on. YAP/TAZ-TEAD complex is a key knot in the Hippo pathway regulating cell proliferation and stem cell functions. Activation or overexpression of this complex has been proved to lead to cell transformation, proliferation and eventually cancerization. In this review, the association between the alterations of hippo pathway and tumorigenesis of various cancer had been elucidated. The structural basis of YAP/TAZ-TEAD complex is analyzed, and the targeting inhibitors are summarized within the medicinal chemistry classification. Moreover, we have also discussed the clinical status and current challenges of these drug candidates, and provide guidance for the future development of inhibitors targeting this pathway, especially YAP/TAZ-TEAD complex.
Asunto(s)
Antineoplásicos , Carcinogénesis , Vía de Señalización Hippo , Neoplasias , Factores de Transcripción de Dominio TEA , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAP , Humanos , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Vía de Señalización Hippo/efectos de los fármacos , Proteínas Señalizadoras YAP/antagonistas & inhibidores , Proteínas Señalizadoras YAP/química , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/antagonistas & inhibidores , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/química , Factores de Transcripción de Dominio TEA/antagonistas & inhibidores , Factores de Transcripción de Dominio TEA/química , Conformación Proteica , Complejos Multiproteicos/antagonistas & inhibidores , Complejos Multiproteicos/químicaRESUMEN
The Hippo tumor-suppressor pathway is frequently dysregulated in human cancers and represents a therapeutic target. However, strategies targeting the mammalian Hippo pathway are limited because of the lack of a well-established cell-surface regulator. Here, we show that transmembrane protein KIRREL1, by interacting with both SAV1 and LATS1/2, promotes LATS1/2 activation by MST1/2 (Hippo kinases), and LATS1/2 activation, in turn, inhibits activity of YAP/TAZ oncoproteins. Conversely, YAP/TAZ directly induce the expression of KIRREL1 in a TEAD1-4-dependent manner. Indeed, KIRREL1 expression positively correlates with canonical YAP/TAZ target gene expression in clinical tumor specimens and predicts poor prognosis. Moreover, transgenic expression of KIRREL1 effectively blocks tumorigenesis in a mouse intrahepatic cholangiocarcinoma model, indicating a tumor-suppressor role of KIRREL1. Hence, KIRREL1 constitutes a negative feedback mechanism regulating the Hippo pathway and serves as a cell-surface marker and potential drug target in cancers with YAP/TAZ dependency.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Carcinogénesis , Proteínas de Ciclo Celular , Vía de Señalización Hippo , Proteínas de la Membrana , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Proteínas de Ciclo Celular/metabolismo , Colangiocarcinoma/metabolismo , Retroalimentación , Humanos , Mamíferos/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas , Factores de Transcripción/metabolismo , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas Señalizadoras YAP/metabolismoRESUMEN
Tumorigenesis is a highly complex process, involving many interrelated and cross-acting signalling pathways. One such pathway that has garnered much attention in the field of cancer research over the last decade is the Hippo signalling pathway. Consisting of two antagonistic modules, the pathway plays an integral role in both tumour suppressive and oncogenic processes, generally via regulation of a diverse set of genes involved in a range of biological functions. This review discusses the history of the pathway within the context of cancer and explores some of the most recent discoveries as to how this critical transducer of cellular signalling can influence cancer progression. A special focus is on the various recent efforts to therapeutically target the key effectors of the pathway in both preclinical and clinical settings.
Asunto(s)
Vía de Señalización Hippo , Neoplasias/tratamiento farmacológico , Animales , Carcinogénesis , Humanos , Neoplasias/metabolismo , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND/AIMS: The Yiqi Huoxue (YQHX) recipe has been shown to attenuate liver fibrosis, but precise mechanisms have not yet been elucidated. Recently, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling has been implicated in liver fibrogenesis. This study investigated whether the YAP/TAZ signaling is involved in the therapeutic effect of YQHX on hepatic fibrosis. MATERIALS AND METHODS: Wistar rats were used to generate a model of carbon tetrachloride (CCl4)-induced liver fibrosis. Chronic hepatitis B (CHB) patients with liver fibrosis were enrolled and assigned to receive either nucleoside/nucleotide analogues (NAs) or NAs plus YQHX. Histology, immunohistochemistry, qRT-PCR, and western blotting were conducted to mechanistically assess the therapeutic effects of YQHX on liver fibrosis. RESULTS: YQHX markedly alleviated morphological alterations in CCl4-induced liver fibrosis and decreased markers of hepatic fibrosis in rats. Furthermore, YQHX significantly suppressed CCl4-meidated activation of the transforming growth factor-beta (TGF-ß)/Smad signaling pathway. Notably, CCl4 induced up-regulation of YAP, TAZ, and connective tissue growth factor (CTGF), which were significantly abrogated by YQHX. Consistent with the above major findings in rats, CHB patients treated with NAs plus YQHX had greater improvement in liver fibrosis than those given NAs alone (71.4% vs. 28.6%; P = 0.057). In addition, hepatic and plasma levels of YAP were significantly decreased after YQHX treatment in CHB patients with liver fibrosis. CONCLUSION: YAP/TAZ signaling plays a role, at least in part, in the anti-fibrotic activity of YQHX. The findings may help to better understand the mechanisms of YQHX in the treatment of liver fibrosis.
Asunto(s)
Antifibróticos , Enfermedad Hepática Inducida por Sustancias y Drogas , Medicamentos Herbarios Chinos , Hepatitis B Crónica , Cirrosis Hepática , Hígado , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAP , Adulto , Animales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antifibróticos/uso terapéutico , Antivirales/uso terapéutico , Tetracloruro de Carbono , Estudios de Casos y Controles , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Quimioterapia Combinada , Medicamentos Herbarios Chinos/uso terapéutico , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/metabolismo , Hepatitis B Crónica/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/etiología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Ratas Wistar , Transducción de Señal , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo , Resultado del Tratamiento , Proteínas Señalizadoras YAP/metabolismoRESUMEN
The transcriptional co-regulators YAP and TAZ pair primarily with the TEAD family of transcription factors to elicit a gene expression signature that plays a prominent role in cancer development, progression and metastasis. YAP and TAZ endow cells with various oncogenic traits such that they sustain proliferation, inhibit apoptosis, maintain stemness, respond to mechanical stimuli, engineer metabolism, promote angiogenesis, suppress immune response and develop resistance to therapies. Therefore, inhibiting YAP/TAZ- TEAD is an attractive and viable option for novel cancer therapy. It is exciting to know that many drugs already in the clinic restrict YAP/TAZ activities and several novel YAP/TAZ inhibitors are currently under development. We have classified YAP/TAZ-inhibiting drugs into three groups. Group I drugs act on the upstream regulators that are stimulators of YAP/TAZ activities. Many of the Group I drugs have the potential to be repurposed as YAP/TAZ indirect inhibitors to treat various solid cancers. Group II modalities act directly on YAP/TAZ or TEADs and disrupt their interaction; targeting TEADs has emerged as a novel option to inhibit YAP/TAZ, as TEADs are major mediators of their oncogenic programs. TEADs can also be leveraged on using small molecules to activate YAP/TAZ-dependent gene expression for use in regenerative medicine. Group III drugs focus on targeting one of the oncogenic downstream YAP/TAZ transcriptional target genes. With the right strategy and impetus, it is not far-fetched to expect a repurposed group I drug or a novel group II drug to combat YAP and TAZ in cancers in the near future.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas de Unión al ADN/antagonistas & inhibidores , Neoplasias/terapia , Transactivadores/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/farmacología , Antineoplásicos/farmacología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Proteínas de Unión al ADN/farmacología , Diseño de Fármacos , Vía de Señalización Hippo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Oncogénicas/efectos de los fármacos , Proteínas Oncogénicas/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Transactivadores/farmacología , Factores de Transcripción/metabolismo , Factores de Transcripción/farmacología , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAPRESUMEN
Harmine (HM) is a ßcarboline alkaloid found in multiple medicinal plants. It has been used in folk medicine for anticancer therapy; however, the molecular mechanism of HM on human breast cancer remains unclear. Transcriptional coactivator with PDZbinding motif (TAZ), also known as WW domaincontaining transcription regulator 1, serves an important role in the carcinogenesis and progression of breast cancer. The aim of the present study was to elucidate the potential anticancer activity and mechanism of HM in breast cancer, in vitro and in vivo. Cell proliferation was measured using a CCK8 assay, apoptotic activity was detected by flow cytometry and DAPI staining, and cell migration was examined using a wound healing assay. The expression of proteins, including extracellular signalregulate kinase (Erk), phosphorylated (p) Erk, protein kinase B (Akt), pAkt, Bcell lymphoma 2 (Bcl2) and Bcl2associated X protein (Bax), were determined by western blotting. The mRNA expression of TAZ was detected using reverse transcriptionquantitative polymerase chain reaction analysis. The expression of proteins in mouse tumor tissues were examined by immunohistochemistry. HM significantly suppressed cellular proliferation and migration, promoted apoptosis in vitro and inhibited tumor growth in vivo. In addition, HM significantly decreased the expression of TAZ, pErk, pAkt and Bcl2, but increased that of Bax. The overexpression of TAZ in breast cancer cells inhibited the antitumor effect of HM. In conclusion, HM was found to induce apoptosis and prevent the proliferation and migration of human breast cancer cell lines, possibly via the downregulation of TAZ.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Harmina/administración & dosificación , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Harmina/farmacología , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Células MCF-7 , Transducción de Señal/efectos de los fármacos , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Three-dimensional (3D) floating culture clumps of mesenchymal stem cell (MSC)/extracellular matrix (ECM) complexes (C-MSCs) consist of cells and self-produced ECM. Previous studies have demonstrated that C-MSCs can be transplanted into bony lesions without an artificial scaffold to induce bone regeneration. Moreover, osteoinductive medium (OIM)-treated C-MSCs (OIM-C-MSCs) have shown rapid and increased new bone formation in vivo. To apply OIM-C-MSCs for novel bone regenerative cell therapy, their cellular properties at the molecular level must be elucidated. The transcriptional co-activators yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) have been recognized as key players in the mechanotransduction cascade, controlling cell lineage commitment in MSCs. It is plausible that 3D C-MSCs/OIM-C-MSCs cultured in floating conditions could provide distinct microenvironments compared to conventional 2D culture systems and thereby induce unique mechanotransduction cascades. Therefore, this study investigated the YAP/TAZ activity in 3D-cultured C-MSCs/OIM-C-MSCs in floating conditions. METHODS: Human bone marrow-derived MSCs were cultured in growth medium supplemented with ascorbic acid. To obtain C-MSCs, confluent cells that had formed on the cellular sheet were scratched using a micropipette tip and were then torn off. The sheet was rolled to make round clumps of cells. Then, YAP/TAZ activity, filamentous actin (F-actin) integrity, collagen type I (COL1) production, and the differentiation potency in 3D floating culture C-MSCs/OIM-C-MSCs were analyzed. RESULTS: C-MSCs cultured in floating conditions lost their actin cytoskeleton to downregulate YAP/TAZ activity, which directed cells to undergo adipogenesis/chondrogenesis. OIM treatment induced abundant COL1 deposition, which facilitated Intß1-dependent actin fiber formation and YAP/TAZ activity to elevate the expression levels of osteogenic master transcriptional factor runt-related transcription factor 2 (RUNX2) mRNA in C-MSCs. Importantly, elevation of YAP/TAZ activity via OIM was associated with COL1 deposition and F-actin integrity, suggesting a positive feedback loop in OIM-C-MSCs. CONCLUSION: These findings suggest that OIM-C-MSCs, which form a unique microenvironment that maintains high YAP/TAZ activity, can serve as better candidates for bone regenerative cell therapy than C-MSCs.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Técnicas de Cultivo de Célula/métodos , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Oseointegración , Fosfoproteínas/metabolismo , Citoesqueleto de Actina/efectos de los fármacos , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Adipogénesis/efectos de los fármacos , Agregación Celular/efectos de los fármacos , Células Cultivadas , Condrogénesis/efectos de los fármacos , Medios de Cultivo/farmacología , Regulación hacia Abajo/efectos de los fármacos , Matriz Extracelular/efectos de los fármacos , Retroalimentación Fisiológica , Humanos , Integrina beta1/metabolismo , Mecanotransducción Celular , Células Madre Mesenquimatosas/efectos de los fármacos , Modelos Biológicos , Oseointegración/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Transducción de Señal , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAP , Quinasas Asociadas a rho/metabolismoRESUMEN
The core components of the Hippo signaling pathway are a cascade of kinases that govern the phosphorylation of downstream transcriptional co-activators, namely, YES-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1, also known as TAZ). The Hippo signaling pathway is considered an important tumor-suppressor pathway, and its dysregulation has been noted in a variety of human cancers, in which YAP/WWTR1 enable cancerous cells to overcome contact inhibition, and to grow and spread uncontrollably. Interestingly, however, recent studies have told a somewhat different but perhaps more intriguing YAP/WWTR1 story, as these studies found that YAP/WWTR1 function as a central hub that integrates signals from multiple upstream signaling pathways, cell-cell interactions and mechanical forces and then bind to and activate different downstream transcriptional factors to direct cell social behavior and cell-cell interactions. In this review, we present the latest findings on the role of YAP/WWTR1 in skin physiology, pathology and tumorigenesis and discuss the statuses of newly developed therapeutic interventions that target YAP/WWTR1 in human cancers, as well as their prospects for use as skin cancer treatments.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Cutáneas/terapia , Factores de Transcripción/metabolismo , Animales , Proteínas de Ciclo Celular , Vía de Señalización Hippo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Terapia Molecular Dirigida , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Transactivadores , Factores de Transcripción/genética , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZRESUMEN
Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) co-operate with numerous transcription factors to regulate gene transcriptions. YAP1 and TAZ are negatively regulated by the tumor suppressive Hippo pathway. In human cancers, the Hippo pathway is frequently deregulated and YAP1 and TAZ escape the inhibition by the Hippo pathway. The upregulation of YAP1 and TAZ induces epithelial-mesenchymal transition and increases drug resistance in cancer cells. TAZ is implicated in cancer stemness. In consequence cancers with hyperactive YAP1 and TAZ are associated with poor clinical prognosis. Inhibitors of YAP1 and TAZ are reasoned to be beneficial in cancer therapy. On the other hand, since YAP1 and TAZ play important roles in the regulation of various tissue stem cells and in tissue repair, activators of YAP1 and TAZ are useful in the regenerative medicine. We discuss the potential application of inhibitors and activators of YAP1 and TAZ in human diseases and review the progress of drug screenings to search for them.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Vía de Señalización Hippo , Humanos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Pronóstico , Medicina Regenerativa , Transducción de Señal , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAPRESUMEN
A diverse range of drug resistance mechanisms in cancer cells and their microenvironment significantly reduces the effectiveness of anti-cancer therapies. Growing evidence suggests that transcriptional effectors of the Hippo pathway, YAP and TAZ, promote resistance to various anti-cancer therapies, including cytotoxic chemotherapy, molecular targeted therapy, and radiation therapy. Here, we overview the role of YAP and TAZ as drug resistance mediators, and also discuss potential upstream regulators and downstream targets of YAP/TAZ in cancer. The widespread involvement of YAP and TAZ in resistance mechanisms suggests that therapeutic targeting of YAP and TAZ may expedite the development of effective anti-resistance therapies.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias/tratamiento farmacológico , Fosfoproteínas/metabolismo , Animales , Antineoplásicos/uso terapéutico , Descubrimiento de Drogas , Resistencia a Antineoplásicos/efectos de los fármacos , Vía de Señalización Hippo , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Terapia Molecular Dirigida , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/radioterapia , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAPRESUMEN
Diabetes and obesity are associated with non-alcoholic steatohepatitis and an increased incidence of hepatocellular carcinoma (HCC). TAZ and YAP are equivalently placed downstream effectors of the Hippo pathway with oncogenic roles in human cancers. Statins are commonly used to patients with metabolic problems as hypercholesterolemia. Statins also have anti-cancer properties, and the cross-talk between mevalonate pathway and Hippo pathway was known. The aim of this study is to confirm the statin's anti-cancer effects on HCC cells and its survival benefits in HCC patients with curative surgery. TAZ expression level in HCC cell lines was analyzed by western blot. Two cell lines (HLF and HuH1) were used in this study. Then the mechanism of statin's anti-proliferative effect was examined in HLF and HuH1 cells. In clinical setting, overall survival and recurrence-free survival (RFS) rate were examined in comparison between statin intake and statin non-intake group. The proliferation assay using four different statins (atorvastatin, pravastatin, fluvastatin, simvastatin). Simvastatin and fluvastatin showed very strong growth suppressive effects, and induced apoptosis in HLF cells, but not HuH1 cells. TAZ expression was suppressed in HLF cells by fluvastatin and simvastatin treatment. The similar change pattern was confirmed in p-ERK1/2 and ERK. In HuH1 cells, such expression change was not confirmed. In clinical setting, statin intake was significantly associated with longer RFS in the HCC patients with hepatectomy (P = 0.038). The statin had the anti-proliferative effects and induced apoptosis in HCC cells and improved the prognosis of HCC patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Factores de Transcripción/metabolismo , Aciltransferasas , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Anciano , Antineoplásicos/farmacología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Hepatectomía , Vía de Señalización Hippo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transactivadores , Factores de Transcripción/genética , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAPRESUMEN
Transcriptional co-activator with PSD-95/Dlg-A/ZO-1 (PDZ)-binding motif (TAZ) regulates in cell proliferation and differentiation. In mesenchymal stem cells it promotes osteogenesis and myogenesis, and suppresses adipogenesis. TAZ activators are expected to prevent osteoporosis, obesity and muscle atrophy. TAZ activation induces epithelial-mesenchymal transition, confers stemness to cancer cells and leads to poor clinical prognosis in cancer patients. In this point of view, TAZ inhibitors should contribute to cancer therapy. Thus, TAZ attracts attention as a two-faced drug target. We screened for TAZ modulators by using human lung cancer A549 cells expressing the fluorescent reporter. Through this assay, we obtained TAZ activator candidates. We unexpectedly found that ethacridine, a widely used antiseptic and abortifacient, enhances the interaction of TAZ and protein phosphatases and increases unphosphorylated and nuclear TAZ. Ethacridine inhibits adipogenesis in mesenchymal C3H10T1/2 cells through the activation of TAZ. This finding suggests that ethacridine is a bona fide TAZ activator and supports that our assay is useful to discover TAZ activators.
Asunto(s)
Adipogénesis/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Etacridina/farmacología , Péptidos y Proteínas de Señalización Intracelular/agonistas , Células Madre Mesenquimatosas/efectos de los fármacos , Proteína Fosfatasa 1/metabolismo , Proteína Fosfatasa 2/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/agonistas , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Genes Reporteros/efectos de los fármacos , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Fosfoproteínas/agonistas , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas/efectos de los fármacos , Proteína Fosfatasa 1/química , Proteína Fosfatasa 1/genética , Proteína Fosfatasa 2/química , Proteína Fosfatasa 2/genética , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Señalizadoras YAPRESUMEN
YAP (Yes-associated protein) and its paralog TAZ (transcriptional co-activator with PDZ-binding motif) are the main downstream effectors of the Hippo signaling pathway. This pathway is an evolutionally conserved signal cascade, which plays pivotal roles in organ size control and tumorigenesis from Drosophila to mammals. Functionally, when the Hippo pathway is activated, YAP and TAZ will be sequestered in the cytoplasm and degraded. Conversely, when the Hippo pathway is deactivated, YAP and TAZ will translocate into nucleus and promote transcription of downstream genes by forming complexes with transcription factors, such as transcriptional enhancer factors (TEF; also referred to as TEAD), runt-domain transcription factors (Runx) and others. Most of these transcription factors belong to growth promoting or apoptosis-inhibition genes. It has been reported that the deactivation of the Hippo pathway, as well as up-regulation of YAP and TAZ was observed in many human cancers with a high frequency, which suggests that the Hippo pathway may be a potent target for developing anticancer drugs. In this review, we provide an overview of the Hippo pathway and summarize recent advances with respect to the role of YAP and TAZ in Hippo signaling pathway and cancer development. Furthermore, we describe the opportunities and challenges for exploit YAP and TAZ as potential therapeutic targets in cancer.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Fosfoproteínas/metabolismo , Transducción de Señal , Animales , Núcleo Celular/metabolismo , Vía de Señalización Hippo , Humanos , Terapia Molecular Dirigida , Tamaño de los Órganos , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Regulación hacia Arriba/efectos de los fármacos , Proteínas Señalizadoras YAPRESUMEN
The transcriptional coactivator with a PDZ-binding motif (TAZ) cooperates with various transcriptional factors and plays various roles. Immortalized human mammalian epithelial MCF10A cells form spheres when TAZ is overexpressed and activated. We developed a cell-based assay using sphere formation by TAZ-expressing MCF10A cells as a readout to screen 18,458 chemical compounds for TAZ activators. Fifty compounds were obtained, and 47 were confirmed to activate the TAZ-dependent TEAD-responsive reporter activity in HEK293 cells. We used the derived subset of compounds as a TAZ activator candidate minilibrary and searched for compounds that promote myogenesis in mouse C2C12 myoblast cells. In this study, we focused on one compound, IBS008738. IBS008738 stabilizes TAZ, increases the unphosphorylated TAZ level, enhances the association of MyoD with the myogenin promoter, upregulates MyoD-dependent gene transcription, and competes with myostatin in C2C12 cells. TAZ knockdown verifies that the effect of IBS008738 depends on endogenous TAZ in C2C12 cells. IBS008738 facilitates muscle repair in cardiotoxin-induced muscle injury and prevents dexamethasone-induced muscle atrophy. Thus, this cell-based assay is useful to identify TAZ activators with a variety of cellular outputs. Our findings also support the idea that TAZ is a potential therapeutic target for muscle atrophy.