RESUMEN
Hyperglycemia is a common feature of diabetes mellitus, considered as a risk factor for cancer. However, its direct effects in cancer cell behavior are relatively unexplored. Herein we show that high glucose concentration induces aberrant glycosylation, increased cell proliferation, invasion and tumor progression of colon cancer. By modulating the activity of the rate-limiting enzyme, glutamine-fructose-6-phosphate amidotransferase (GFAT), we demonstrate that hexosamine biosynthetic pathway (HBP) is involved in those processes. Biopsies from patients with colon carcinoma show increased levels of GFAT and consequently aberrant glycans' expression suggesting an increase of HBP flow in human colon cancer. All together, our results open the possibility that HBP links hyperglycemia, aberrant glycosylation and tumor malignancy, and suggest this pathway as a potential therapeutic target for colorectal cancer.
RESUMEN
Cdc kinase subunit (Cks) proteins Cks1 and Cks2 are adaptor-like proteins that bind many cyclin-dependent kinases. A wealth of clinical data has shown that Cks proteins are overexpressed in many types of human cancers and this often correlates with increased tumor aggressiveness. Previously, we showed that Cks overexpression abrogates the intra-S-phase checkpoint, a major barrier to oncogene-mediated transformation. Interestingly, the intra-S-phase checkpoint is crucial for the cellular response to replication stress, a major pathway of apoptosis induction by many chemotherapeutic agents. Here, we demonstrate cancer cells that overexpress Cks1 or Cks2 override the intra-S-phase checkpoint in the presence of replication stress-inducing chemotherapies such as 5-Fluorouracil (5-FU) and methotrexate (MTX) leading to enhanced sensitivity in vitro and in vivo. Furthermore, enforced expression of Cks1 in an MTX-resistant breast cancer cell line was found to restore drug sensitivity. Our results suggest that Cks proteins are important determinants of apoptosis induction of replication stress-inducing chemotherapies such as 5-FU.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Quinasas Ciclina-Dependientes/biosíntesis , Daño del ADN , Fluorouracilo/farmacología , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/genética , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/metabolismo , Replicación del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The nuclear factor of activated T cells (NFAT) family of transcription factors has been primarily identified in immune cells; however, these proteins have been recently found to be functionally active in several other non-immune cell types. NFAT proteins are activated upon different stimuli that lead to increased intracellular calcium levels. Regardless of their widely known cytokine gene expression properties, NFATs have been shown to regulate other genes related to cell cycle progression, cell differentiation and apoptosis, revealing a broader role for these proteins in normal cell physiology. Several reports have addressed the participation of NFATs in many aspects of malignant cell transformation and tumorigenic processes. In this review, we will discuss the involvement of the different NFAT family members in the regulation of cell cycling, differentiation and tumor formation, and also its implications on oncogenesis. Better understanding the mechanisms by which NFATs regulate cell cycle and tumor-related events should be relevant for the development of rational anti-cancer therapies.
Asunto(s)
Transformación Celular Neoplásica/metabolismo , Regulación Neoplásica de la Expresión Génica , Activación de Linfocitos , Factores de Transcripción NFATC/fisiología , Linfocitos T CD4-Positivos/metabolismo , Transformación Celular Neoplásica/genética , Humanos , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismoRESUMEN
The nuclear factor of activated T cells (NFAT) family of transcription factors has been primarily identified in immune cells; however, these proteins have been recently found to be functionally active in several other non-immune cell types. NFAT proteins are activated upon different stimuli that lead to increased intracellular calcium levels. Regardless of their widely known cytokine gene expression properties, NFATs have been shown to regulate other genes related to cell cycle progression, cell differentiation and apoptosis, revealing a broader role for these proteins in normal cell physiology. Several reports have addressed the participation of NFATs in many aspects of malignant cell transformation and tumorigenic processes. In this review, we will discuss the involvement of the different NFAT family members in the regulation of cell cycling, differentiation and tumor formation, and also its implications on oncogenesis. Better understanding the mechanisms by which NFATs regulate cell cycle and tumor-related events should be relevant for the development of rational anti-cancer therapies.