![]() ![]() Multiple ULK1 and VPS34 inhibitors are in pre-clinical evaluation. The ULK/FIP200/ATG13 complex induces vesicle nucleation, which continues with involvement of the BECN1 complex which includes VPS34. Each stage has potential clinical targets. The process of autophagy is divided into five distinct stages: initiation, nucleation, expansion and elongation, closure and fusion, and cargo degradation. Importantly, while blocking autophagy at any stage should be similarly effective at preventing degradation of autophagic cargos, recent work raises the possibility that biological effects on tumor cell behavior may be different when the autophagy pathway is blocked at different stages. This breakdown of stages is important as each stage has a subset of potential therapeutic targets for inhibiting autophagy in humans. Autophagy related ( ATG) genes are evolutionarily conserved and tightly regulate the production of autophagosomes, which is divided into five distinct stages: initiation, nucleation of the autophagosome, expansion and elongation of the autophagosome membrane, closure and fusion with the lysosome, and degradation of intravesicular products. Autophagy occurs at a basal level in all cells and can be induced by various signals and cellular stresses. Macroautophagy (referred to hereafter as autophagy) is a highly conserved catabolic process with the formation of double membrane vesicles called autophagosomes that engulf cellular proteins and organelles for delivery to the lysosome (Fig. In this review, we focus on how we may be able to leverage our understanding of these interactions and mechanisms to better harness the power of autophagy manipulation in cancer care. Additionally, we now have a better mechanistic understanding of how autophagy interacts with cell death pathways to alter therapeutic responses to cancer treatments. Autophagy can have both tumor cell autonomous and non-autonomous promoting effects on tumor growth and both the degradative process of autophagy itself related but distinct degradative processes as well as non-degradative activities of the autophagy machinery can affect tumor cell behavior. These studies focus on blocking the recycling mechanism of autophagy to prevent the renewal of cellular proteins and other molecules that help cancer cells survive under stressful conditions such as hypoxia, nutrient deprivation and to enhance other cancer treatments including chemotherapy and radiation. Conversely, in advanced cancers, while both enhancing autophagy and inhibiting it have been proposed as therapeutic strategies, clinical interventions to deliberately manipulate autophagy in cancer therapy are already underway with the vast majority focused on inhibiting autophagy. Thus, in premalignant lesions, enhancing autophagy might prevent cancer. Once malignant cancers are fully established, increased autophagy enables tumor cell survival and growth. For example, decreased autophagy is associated with infiltration of regulatory T cells that suppress the immune system and decrease effective immunosurveillance allowing for increased tumor initiation. Autophagy also works with immunosurveillance to provide a non-cellular autonomous cancer prevention method. This helps prevent chronic cellular damage and transition into a cancer-initiating cell. Autophagy maintains normal cell homeostasis through the removal of oncogenic protein substrates, toxic unfolded proteins and damaged organelles. It is felt that autophagy is an important mechanism to prevent cancer development in both cell autonomous and non-cell autonomous methods. Indeed, although it is well accepted that autophagy is important in many diseases, until now, the majority of clinical studies that involve deliberate attempts to manipulate autophagy are in cancer therapy, almost always in patients with advanced disease. Its role in cancer therapy is particularly important. ![]() In 2016, Yoshinori Ohsumi was awarded the Nobel Prize for Physiology or Medicine for his work on autophagy and its impact in the study of human health and disease. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |