RESUMEN
Conventionally, Rho guanine nucleotide exchange factors (GEFs) are known activators of Rho guanosine triphosphatases (GTPases) that promote tumorigenesis. However, the role of Rho GEFs in non-small cell lung cancer (NSCLC) remains largely unknown. Through the screening of 81 Rho GEFs for their expression profiles and correlations with survival, four of them were identified with strong significance for predicting the prognosis of NSCLC patients. The four Rho GEFs, namely ABR, PREX1, DOCK2 and DOCK4, were downregulated in NSCLC tissues compared to normal tissues. The downregulation of ABR, PREX1, DOCK2 and DOCK4, which can be attributfed to promoter methylation, is correlated with poor prognosis. The underexpression of the four key Rho GEFs might be related to the upregulation of MYC signaling and DNA repair pathways, leading to carcinogenesis and poor prognosis. Moreover, overexpression of ABR was shown to have a tumor-suppressive effect in PC9 and H1703 cells. In conclusion, the data reveal the unprecedented role of ABR as tumor suppressor in NSCLC. The previously unnoticed functions of Rho GEFs in NSCLC will inspire researchers to investigate the distinct roles of Rho GEFs in cancers, in order to provide critical strategies in clinical practice.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , Factores de Intercambio de Guanina Nucleótido Rho/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Metilación de ADN/genética , Progresión de la Enfermedad , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Pronóstico , Regiones Promotoras Genéticas/genética , Dominios Proteicos , Factores de Intercambio de Guanina Nucleótido Rho/química , Factores de Intercambio de Guanina Nucleótido Rho/genéticaRESUMEN
Despite treatment advances, radioresistance and metastasis markedly impair the benefits of radiotherapy to patients with malignancies. Functioning as molecular switches, Rho guanosine triphosphatases (GTPases) have well-recognized roles in regulating various downstream signaling pathways in a wide range of cancers. In recent years, accumulating evidence indicates the involvement of Rho GTPases in cancer radiotherapeutic efficacy and metastasis, as well as radiation-induced metastasis. The functions of Rho GTPases in radiotherapeutic efficacy are divergent and context-dependent; thereby, a comprehensive integration of their roles and correlated mechanisms is urgently needed. This review integrates current evidence supporting the roles of Rho GTPases in mediating radiotherapeutic efficacy and the underlying mechanisms. In addition, their correlations with metastasis and radiation-induced metastasis are discussed. Under the prudent application of Rho GTPase inhibitors based on critical evaluations of biological contexts, targeting Rho GTPases can be a promising strategy in overcoming radioresistance and simultaneously reducing the metastatic potential of tumor cells.
Asunto(s)
Neoplasias/enzimología , Neoplasias/radioterapia , Proteínas de Unión al GTP rho/metabolismo , Animales , Humanos , Metástasis de la Neoplasia , Neoplasias/patología , Tolerancia a RadiaciónRESUMEN
Despite therapeutic advances, resistance to chemotherapy remains a major challenge to patients with malignancies. Rho GTPases are essential for the development and progression of various diseases including cancer, and a vast number of studies have linked Rho GTPases to chemoresistance. Therefore, understanding the underlying mechanisms can expound the effects of Rho GTPases towards chemotherapeutic agents, and targeting Rho GTPases is a promising strategy to downregulate the chemo-protective pathways and overcome chemoresistance. Importantly, exceptions in certain biological conditions and interactions among the members of Rho GTPases should be noted. In this review, we focus on the role of Rho GTPases, particularly Rac1, in regulating chemoresistance and provide an overview of their related mechanisms and available inhibitors, which may offer novel options for future targeted cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Neoplasias/patología , Proteínas de Unión al GTP rho/metabolismo , Animales , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Transducción de SeñalRESUMEN
Development of chemoresistance remains a major challenge in treating esophageal squamous cell carcinoma (ESCC) patients despite treatment advances. However, the role of RAC1 in chemoresistance of ESCC and the underlying mechanisms remain largely unknown. In this study, we found that higher levels of RAC1 expression were associated with poorer prognosis in ESCC patients. Enhanced RAC1 expression increased cell proliferation, migration, and chemoresistance in vitro. Combination therapy using RAC1 inhibitor EHop-016 and cisplatin significantly promoted cell viability inhibition, G2/M phase cycle arrest, and apoptosis when compared to each monotherapy. Mechanistically, glycolysis was significantly downregulated in the RAC1 inhibitor monotherapy group and the combination group via inhibiting AKT/FOXO3a signaling when compared to the control group. Moreover, the silencing of RAC1 inhibited AKT/FOXO3a signaling and cell glycolysis while the upregulation of RAC1 produced an opposite effect. In murine xenograft models, the tumor volume and the expression of glycolytic enzymes were significantly reduced in combination therapy when compared to each monotherapy group. Overall, our study demonstrates that targeting RAC1 with an inhibitor overcomes cisplatin resistance in ESCC by suppressing glycolytic enzymes, which provides a promising strategy for treatment of ESCC in clinical practice.
