RESUMO
Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFß signature genes. Excess glucose was found to promote EMT through autocrine TGFß stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target.Significance: A glucose-transforming pathway in TGFß-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. Cancer Res; 78(7); 1604-18. ©2018 AACR.
Assuntos
Aldeído Redutase/genética , Neoplasias do Colo/patologia , Transição Epitelial-Mesenquimal/genética , L-Iditol 2-Desidrogenase/genética , Neoplasias Pulmonares/patologia , Células A549 , Animais , Linhagem Celular Tumoral , Glucose/metabolismo , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Células MCF-7 , Camundongos , Interferência de RNA , RNA Interferente Pequeno/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis. Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects. Accordingly, we conclude that different EMT-TFs have complementary subfunctions in driving pancreatic tumour metastasis. Therapeutic strategies should consider these potential specificities of EMT-TFs to target these factors simultaneously.
Assuntos
Movimento Celular , Plasticidade Celular , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/metabolismo , Neoplasias Experimentais/metabolismo , Neoplasias Pancreáticas/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Proliferação de Células , Genes p53 , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos Transgênicos , Mutação , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genética , Interferência de RNA , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Tempo , Transativadores/genética , Transfecção , Carga Tumoral , Células Tumorais Cultivadas , Proteína 1 Relacionada a Twist/genética , Proteína 1 Relacionada a Twist/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genéticaRESUMO
Approximately 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with poor clinical response to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs) that synergize with ionizing radiation (IR) ("radiosensitizers") that could be incorporated into current treatment strategies for locally advanced rectal cancers (LARCs) expressing mutant K-RAS. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5-fluorouracil (5-FU), which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC.
