Nejvíce citovaný článek - PubMed ID 12694561
Information about cholesterol subcellular localization and transport pathways inside cells is essential for understanding and treatment of cholesterol-related diseases. However, there is a lack of reliable tools to monitor it. This work follows the fate of Sterolight, a BODIPY-labelled sterol, within the cell and demonstrates it as a suitable probe for visualization of sterol/lipid trafficking. Sterolight enters cells through an energy-independent process and knockdown experiments suggest caveolin-1 as its potential cellular carrier. Intracellular transport of Sterolight is a rapid process, and transfer from ER and mitochondria to lysosomes and later to lipid droplets requires the participation of active microtubules, as it can be inhibited by the microtubule disruptor nocodazole. Excess of the probe is actively exported from cells, in addition to being stored in lipid droplets, to re-establish the sterol balance. Efflux occurs through a mechanism requiring energy and may be selectively poisoned with verapamil or blocked in cells with mutated cholesterol transporter NPC1. Sterolight is efficiently transferred within and between different cell populations, making it suitable for monitoring numerous aspects of sterol biology, including the live tracking and visualization of intracellular and intercellular transport.
Autophagy is best known for its role in organelle and protein turnover, cell quality control, and metabolism. The autophagic machinery has, however, also adapted to enable protein trafficking and unconventional secretory pathways so that organelles (such as autophagosomes and multivesicular bodies) delivering cargo to lysosomes for degradation can change their mission from fusion with lysosomes to fusion with the plasma membrane, followed by secretion of the cargo from the cell. Some factors with key signalling functions do not enter the conventional secretory pathway but can be secreted in an autophagy-mediated manner.Positive clinical results of some autophagy inhibitors are encouraging. Nevertheless, it is becoming clear that autophagy inhibition, even within the same cancer type, can affect cancer progression differently. Even next-generation inhibitors of autophagy can have significant non-specific effects, such as impacts on endosome-related secretory pathways and secretion of extracellular vesicles (EVs). Many studies suggest that cancer cells release higher amounts of EVs compared to non-malignant cells, which makes the effect of autophagy inhibitors on EVs secretion highly important and attractive for anticancer therapy. In this review article, we discuss how different inhibitors of autophagy may influence the secretion of EVs and summarize the non-specific effects of autophagy inhibitors with a focus on endosome-related secretory pathways. Modulation of autophagy significantly impacts not only the quantity of EVs but also their content, which can have a deep impact on the resulting pro-tumourigenic or anticancer effect of autophagy inhibitors used in the antineoplastic treatment of solid cancers.
- Klíčová slova
- Amphisomes, Autophagy, Autophagy inhibitors, Cancer, Endosomes, Exosomes, Extracellular vesicles, Multivesicular bodies, Non-conventional secretory pathways,
- MeSH
- autofagie účinky léků MeSH
- autofagozomy metabolismus MeSH
- cílená molekulární terapie * MeSH
- endocytóza účinky léků MeSH
- endozomy metabolismus MeSH
- exozómy metabolismus MeSH
- lidé MeSH
- nádory farmakoterapie etiologie metabolismus MeSH
- progrese nemoci MeSH
- proteolýza MeSH
- protinádorové látky farmakologie terapeutické užití MeSH
- sekreční dráha účinky léků MeSH
- signální transdukce účinky léků MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- protinádorové látky MeSH
