RESUMEN
Human T-cell leukemia virus type 1 (HTLV-I) is associated with adult T-cell leukemia (ATL), an aggressive lymphoproliferative disease with a dismal prognosis. We have previously described the presence of Notch1 activating mutations and constitutive Notch1 signaling in patients with acute ATL. In this study, we report a high frequency of F-box and WD repeat domain containing 7 (FBXW7)/hCDC4 mutations within the WD40 substrate-binding domain in 8 of 32 acute ATL patients (25%). Functionally, ATL FBXW7 mutants lost their ability to interact with intracellular Notch (NICD), resulting in increased protein stability and constitutive Notch1 signaling. Consistent with the loss-of-function found in ATL patients, expression of WT FBXW7 in several patient-derived ATL lines demonstrated strong tumor-suppressor activity characterized by reduced proliferation of ATL cells. Remarkably, two FBXW7 mutants, D510E and D527G, demonstrated oncogenic activity when expressed in the presence of HTLV-I Tax, mutated p53 R276H, or c-Myc F138C found in human cancers. Transforming activity was further demonstrated by the ability of the FBXW7 D510E mutant to provide IL-2-independent growth of Tax-immortalized human T cells and increase the tumor formation in a xenograft mouse model of ATL. This study suggests that FBXW7, normally a tumor suppressor, can act as an oncogene when mutated and may play an important role in the pathogenesis of ATL.
Asunto(s)
Proteínas de Ciclo Celular , Proteínas F-Box , Leucemia-Linfoma de Células T del Adulto , Mutación Missense , Ubiquitina-Proteína Ligasas , Adulto , Sustitución de Aminoácidos , Animales , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proteínas F-Box/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD , Femenino , Xenoinjertos , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Interleucina-2/genética , Interleucina-2/metabolismo , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma de Células T del Adulto/patología , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Dominios Proteicos , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Ratas , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transducción de Señal/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: Non-small cell lung cancer (NSCLC) is a very aggressive and histologically heterogeneous type of lung cancer. The main problem in the treatment of NSCLC is chemoresistance and metastasis. Compared to other malignant tumors, many molecular mechanisms are dysfunctional in NSCLC. Epidermal growth factor receptor (EGFR) is one of the most frequently mutated genes in NSCLC. MATERIALS AND METHODS: We investigated the effect of afatinib the against A549 NSCLC cell line, because it is active against mutated EGFR. Moreover, we aimed to investigate the mRNA level of HSPA5 (one of the heat shock proteins that can contribute in the down-regulation of the EGF-signaling pathway) before and after afatinib treatment. RESULTS: Afatinib treatment induced apoptosis and decreased levels of HSPA5 mRNA in cancer cells. CONCLUSION: Advanced analysis, might be helpful in understanding the mechanisms of relations between tyrosine kinase inhibition of EGFR and HSPA5 in lung cancer cells.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/farmacología , Células A549 , Afatinib , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Chaperón BiP del Retículo Endoplásmico , Receptores ErbB/genética , Proteínas de Choque Térmico/genética , Humanos , Neoplasias Pulmonares/genética , Mutación/efectos de los fármacos , Mutación/genética , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
The Notch signaling pathway is deregulated in numerous solid types of cancer including non-small cell lung cancer (NSCLC). However, the profile of Notch ligand expression remains unclear. Therefore, the present study aimed to determine the profile of Notch ligands in NSCLC patients and to investigate whether quantitative assessment of Notch ligand expression may have prognostic significance in NSCLC patients. The study was performed in 61 pairs of tumor and matched unaffected lung tissue specimens obtained from patients with various stages of NSCLC, which were analyzed by reverse transcription-polymerase chain reaction. The marked expression levels of certain analyzed genes were detected in NSCLC samples and in noncancerous lung samples. Of the five Notch ligands, jagged 1 (Jag1), jagged 2, delta-like protein 1 and delta-like protein 4 were expressed in the majority of tissues, but their expression levels were reduced in NSCLC when compared with noncancerous lung tissue (P<0.001). Delta-like protein 3 expression was consistently low and was observed only in 21/61 tumor tissue samples. Taken together, Notch ligands are expressed in NSCLC. However, the expression level is reduced when compared to noncancerous tissue. Furthermore, the present study revealed that quantitative assessment of Jag1 expression in NSCLC may improve prognostication of patient survival.
RESUMEN
Lung cancer is the most common reason of cancer deaths and about 85% of these are non-small-cell lung cancer. Currently, lung cancer therapy is mainly based on the tumor node metastasis (TNM) disease staging and tumor histological classification. Despite therapeutic innovations, the prognosis for lung cancer patients has not significantly changed in the last years. Therefore, a proper understanding of cell signaling pathways involved in cancer pathogenesis seems to be essential for improvement in cancer therapy field. The knowledge of crosstalk between epidermal growth factor receptor (EGFR) and Notch pathway can lead to enhanced screening for the expression of these genes allowing patients to optimize treatment options and predict potential treatment resistance. This review focuses on recent advances related to the mechanisms of EGFR and Notch signaling in non-small-cell lung cancer and the effectiveness of current Notch- and EGFR-targeted therapies.