RESUMO
Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.
RESUMO
Mitochondrial respiratory supercomplex formation requires HIG2A protein, which also has been associated with cell proliferation and cell survival under hypoxia. HIG2A protein localizes in mitochondria and nucleus. DNA methylation and mRNA expression of the HIGD2A gene show significant alterations in several cancers, suggesting a role for HIG2A in cancer biology. The present work aims to understand the dynamics of the HIG2A subcellular localization under cellular stress. We found that HIG2A protein levels increase under oxidative stress. H2O2 shifts HIG2A localization to the mitochondria, while rotenone shifts it to the nucleus. HIG2A protein colocalized at a higher level in the nucleus concerning the mitochondrial network under normoxia and hypoxia (2% O2). Hypoxia (2% O2) significantly increases HIG2A nuclear colocalization in C2C12 cells. In HEK293 cells, chemical hypoxia with CoCl2 (>1% O2) and FCCP mitochondrial uncoupling, the HIG2A protein decreased its nuclear localization and shifted to the mitochondria. This suggests that the HIG2A distribution pattern between the mitochondria and the nucleus depends on stress and cell type. HIG2A protein expression levels increase under cellular stresses such as hypoxia and oxidative stress. Its dynamic distribution between mitochondria and the nucleus in response to stress factors suggests a new communication system between the mitochondria and the nucleus.
Assuntos
Núcleo Celular/metabolismo , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Estresse Oxidativo , Animais , Hipóxia Celular , Células HEK293 , Humanos , Camundongos , Modelos Biológicos , Transporte Proteico , Frações Subcelulares/metabolismoRESUMO
Tumor cells can employ epithelial-mesenchymal transition (EMT) or autophagy in reaction to microenvironmental stress. Importantly, EMT and autophagy negatively regulate each other, are able to interconvert, and both have been shown to contribute to drug-resistance in glioblastoma (GBM). EMT has been considered one of the mechanisms that confer invasive properties to GBM cells. Autophagy, on the other hand, may show dual roles as either a GBM-promoter or GBM-suppressor, depending on microenvironmental cues. The Wingless (WNT) signaling pathway regulates a plethora of developmental and biological processes such as cellular proliferation, adhesion and motility. As such, GBM demonstrates deregulation of WNT signaling in favor of tumor initiation, proliferation and invasion. In EMT, WNT signaling promotes induction and stabilization of different EMT activators. WNT activity also represses autophagy, while nutrient deprivation induces ß-catenin degradation via autophagic machinery. Due to the importance of the WNT pathway to GBM, and the role of WNT signaling in EMT and autophagy, in this review we highlight the effects of the WNT signaling in the regulation of both processes in GBM, and discuss how the crosstalk between EMT and autophagy may ultimately affect tumor biology.
RESUMO
During tumorigenesis, cancer cells are exposed to a wide variety of intrinsic and extrinsic stresses that challenge homeostasis and growth. Cancer cells display activation of distinct mechanisms for adaptation and growth even in the presence of stress. Autophagy is a catabolic mechanism that aides in the degradation of damaged intracellular material and metabolite recycling. This activity helps meet metabolic needs during nutrient deprivation, genotoxic stress, growth factor withdrawal and hypoxia. However, autophagy plays a paradoxical role in tumorigenesis, depending on the stage of tumor development. Early in tumorigenesis, autophagy is a tumor suppressor via degradation of potentially oncogenic molecules. However, in advanced stages, autophagy promotes the survival of tumor cells by ameliorating stress in the microenvironment. These roles of autophagy are intricate due to their interconnection with other distinct cellular pathways. In this review, we present a broad view of the participation of autophagy in distinct phases of tumor development. Moreover, autophagy participation in important cellular processes such as cell death, metabolic reprogramming, metastasis, immune evasion and treatment resistance that all contribute to tumor development, is reviewed. Finally, the contribution of the hypoxic and nutrient deficient tumor microenvironment in regulation of autophagy and these hallmarks for the development of more aggressive tumors is discussed.