1,721,043 research outputs found
Autophagy up and down by outsmarting the incredible ULK
No full text: Macroautophagy/autophagy initiation is finely regulated by post-translational modifications of key proteins, to comply with the fast kinetics of the cellular response to several stress stimuli. Phosphorylation and ubiquitination play a central role in controlling autophagy by influencing the activity, recruitment and turnover of autophagic components. Recently, we found that, upon autophagy progression, ULK1 kinase is specifically ubiquitinated by the E3 ligase NEDD4L and then degraded via the proteasome. However, during prolonged autophagy, while the ULK1 protein undergoes this inhibition, ULK1 mRNA is actively transcribed, translated and then inhibited again by MTOR-dependent inhibitory phosphorylation. This regulation is essential to promptly restore the ULK1 protein to its original levels to keep autophagy under a safe and physiological threshold
Connecting autophagy: AMBRA1 and its network of regulation
No full text: During autophagy, a double-membraned vesicle called the autophagosome is responsible for the degradation of long-lived proteins and damaged/old organelles, thus contributing to the maintenance of cellular homeostasis. Physiological stimuli and stressors enhance autophagy in order to accomplish important processes such as cell differentiation or as a cytoprotective response. In line with this, numerous studies have demonstrated the relevance of proper autophagy regulation to health. Autophagy defects are associated with the insurgence of neurological/neurodegenerative diseases and cancer. Moreover, the autophagy pathway is often potentiated in cancer cells to increase cell survival. Increased knowledge of the molecular mechanisms underlying autophagy regulation and their interplay with other cellular pathways would provide advances in cancer treatment. In this context, post-translational modifications, protein-protein interactions, and regulative feedback loops offer promising insights. In this review, we focus on AMBRA1, a proautophagic protein that was recently demonstrated to participate in numerous crucial regulative mechanisms of the autophagy process
ULK1 ubiquitylation is regulated by phosphorylation on its carboxy terminus
No full text: Autophagy is a highly conserved process that acts sequestering cytoplasmic components for their degradation by the lysosomes. It consists of several sequential steps that have to be finely regulated to ensure both its progression and termination. Post-translational modifications (PTMs) play an important role in regulating ATG proteins function in different stages of autophagy. Recently, we demonstrated that, during prolonged starvation, ULK1 protein is specifically ubiquitylated by NEDD4L, and that this regulation is important to protect cells against excessive autophagy. In this Extra view, we show that ULK1 phosphorylation at 3 different sites on the same ULK1 target region for NEDD4L is preparatory for its ubiquitylation and subsequent degradation. This adds to the complexity of ULK1 multi-level regulation by several factors, including kinases, phosphatases and acetylases, with each contributing to autophagy homeostasis
The Close interconnection between mitochondrial dynamics and mitophagy in cancer
Full text linkRecent decades have revealed the shape changes of mitochondria and their regulators to be main players in a plethora of physiological cell processes. Mitochondria are extremely dynamic organelles whose highly controlled morphological changes respond to specific and diverse pathophysiological needs. Thus, their qualitative control is crucial for the determination of cell function and fate. Moreover, ever-new metabolic changes, mainly attributable to mitochondrial (dys)functions, are strongly connected to cancer and its microenvironment. For this reason, the aspects controlling mitochondria activity and status are in the oncological spotlight. In this review, we elucidate the most intriguing discoveries related to two apparently independent but strictly interconnected processes crucial for the organelle functionality and fate, mitochondrial dynamics, and mitophagy. We will mostly focus on their metabolic interconnections and regulations that can causally foster a tumoral context
The mitochondrial dynamics in cancer and immune-surveillance
Full text linkMitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system. By this review, we overview how mitochondrial dynamics can affect various processes during cancer development, acting directly on tumor cells or indirectly on cells responsible for tumor aggression and defence
Recent advances in understanding the role of autophagy in paediatric brain tumours
No full textAutophagy is a degradative process occurring in eukaryotic cells to maintain homeostasis and cell survival. After stressful conditions including nutrient deprivation, hypoxia or drugs administration, autophagy is induced to counteract pathways that could lead to cell death. In cancer, autophagy plays a paradoxical role, acting both as tumour suppressor-by cleaning cells from damaged organelles and inhibiting inflammation or, alternatively, by promoting genomic stability and tumour adaptive response-or as a pro-survival mechanism to protect cells from stresses such as chemotherapy. Neural-derived paediatric solid tumours represent a variety of childhood cancers with unique anatomical location, cellular origins, and clinical presentation. These tumours are a leading cause of morbidity and mortality among children and new molecular diagnostics and therapies are necessary for longer survival and reduced morbidity. Here, we review advances in our understanding of how autophagy modulation exhibits antitumor properties in experimental models of paediatric brain tumours, i.e., medulloblastoma (MB), ependymoma (EPN), paediatric low-grade and high-grade gliomas (LGGs, HGGs), atypical teratoid/rhabdoid tumours (ATRTs), and retinoblastoma (RB). We also discuss clinical perspectives to consider how targeting autophagy may be relevant in these specific paediatric tumours
Mitochondrial Transfer as a Strategy for Enhancing Cancer Cell Fitness:Current Insights and Future Directions
Full text linkIt is now recognized that tumors are not merely masses of transformed cells but are intricately interconnected with healthy cells in the tumor microenvironment (TME), forming complex and heterogeneous structures. Recent studies discovered that cancer cells can steal mitochondria from healthy cells to empower themselves, while reducing the functions of their target organ. Mitochondrial transfer, i.e. the intercellular movement of mitochondria, is recently emerging as a novel process in cancer biology, contributing to tumor growth, metastasis, and resistance to therapy by shaping the metabolic landscape of the tumor microenvironment. This review highlights the influence of transferred mitochondria on cancer bioenergetics, redox balance and apoptotic resistance, which collectively foster aggressive cancer phenotype. Furthermore, the therapeutic implications of mitochondrial transfer are discussed, emphasizing the potential of targeting these pathways to overcome drug resistance and improve treatment efficacy
Autophagy and Exosomes Relationship in Cancer: Friends or Foes?
Full text linkAutophagy is an intracellular degradation process involved in the removal of proteins and damaged organelles by the formation of a double-membrane vesicle named autophagosome and degraded through fusion with lysosomes. An intricate relationship between autophagy and the endosomal and exosomal pathways can occur at different stages with important implications for normal physiology and human diseases. Recent researches have revealed that extracellular vesicles (EVs), such as exosomes, could have a cytoprotective role by inducing intracellular autophagy; on the other hand, autophagy plays a crucial role in the biogenesis and degradation of exosomes. Although the importance of these processes in cancer is well established, their interplay in tumor is only beginning to be documented. In some tumor contexts (1) autophagy and exosome-mediated release are coordinately activated, sharing the molecular machinery and regulatory mechanisms; (2) cancer cell-released exosomes impact on autophagy in recipient cells through mechanisms yet to be determined; (3) exosome-autophagy relationship could affect drug resistance and tumor microenvironment (TME). In this review, we survey emerging discoveries relevant to the exosomes and autophagy crosstalk in the context of cancer initiation, progression and recurrence. Consequently, we discuss clinical implications by targeting autophagy-exosomal pathway interaction and how this could lay a basis for the purpose of novel cancer therapeutics
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