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Cancer cells are characterized by altered energetic metabolism with increasing glucose uptake. F806, a 16‐membered macrodiolide analogue, has anti‐tumour effects on oesophageal squamous cell carcinoma (ESCC) cells. However, its precise anti‐tumour mechanism remains unclear. Here, metascape analysis of our previous quantitative proteomics data showed that F806 induced glucose starvation response and inhibited energy production in ESCC cells. The reduced glucose uptake and ATP production were further validated by the fluorescent methods, using glucose‐conjugated bioprobe Glu‐1‐O‐DCSN, and the bioluminescent methods, respectively. Consistently, under F806 treatment the AMP‐activated protein kinase signalling was activated, and autophagy flux was promoted and more autophagosomes were formed. Moreover, live‐cell imaging and immunofluorescence analysis showed that F806 induced GLUT1 plasma membrane dissociation and promoted its internalization and autolysosome accumulation and lysosome degradation. Furthermore, molecular docking studies demonstrated that F806 bound to GLUT1 with a comparable binding energy to that of GLUT1's direct interacting inhibitor cytochalasin B. Amino acid mutation was used to test which residues of GLUT1 may participate in F806 mediated‐GLUT1 internalization and degradation, and results showed that Thr137, Asn411 and Trp388 were required for GLUT1 internalization and degradation, respectively. Taken together, these findings shed light on a novel anti‐tumour mechanism of F806 by targeting and promoting GLUT1 internalization and further autolysosomal degradation. [ABSTRACT FROM AUTHOR]

Autophagy is an important tightly controlled cellular process that regulates cellular homeostasis and is involved in deciding cell fate such as cell survival and death. The role of autophagy in many intracellular signaling pathways explains its interaction with other different types of cell death, including apoptosis and immunogenic cell death (ICD). The reports showed the complex and intriguing relationship existing between autophagy and immune system signaling pathways. However, the role of autophagy in ICD remains to be clearly elucidated. In this study, we demonstrated that Brucine, a clinically-used small molecule in traditional Chinese medicine, elicited autophagy inhibition. Brucine also triggered cell stress and induced features of ICD, including calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release in MDA-MB-231 and CT26 cancer cells. Brucine impaired autolysosomal degradation and exerted a feedback regulation of ERK1/2-mTOR-p70S6K signaling cascade. Brucine-elicited ICD was confirmed by the rejection of CT26 tumor cells, implanted in the mice after vaccination with Brucine-treated CT26 cells. The impaired autophagy contributed to Brucine-induced ICD, as knock-down of Atg5 significantly reduced Brucine-elicited CRT exposure and HMGB1 release. Our results revealed Brucine as a novel autophagy regulator, ICD inducer and hitherto undocumented role of autophagy in ICD. Thus, these results imply the importance of Brucine in cancer immunotherapy. Therefore, Brucine may be used as an ICD inducer and improve its application in cancer treatment with minimized toxicity. [ABSTRACT FROM AUTHOR]

Dihydroartemisinin (DHA) is an active metabolite of sesquiterpene trioxane lactone extracted from Artemisia annua, which is used to treat malaria worldwide. DHA can activate autophagy, which is the main mechanism to remove the damaged cell components and recover the harmful or useless substances from eukaryotic cells and maintain cell viability through the autophagy lysosomal degradation system. Autophagy activation and autophagy flux correction are playing an important neuroprotective role in the central nervous system, as they accelerate the removal of toxic protein aggregates intracellularly and extracellularly to prevent neurodegenerative processes, such as Alzheimer's disease (AD). In this study, we explored whether this mechanism can mediate the neuroprotective effect of DHA on the AD model in vitro and in vivo. Three months of DHA treatment improved the memory and cognitive impairment, reduced the deposition of amyloid β plaque, reduced the levels of Aβ40 and Aβ42, and ameliorated excessive neuron apoptosis in APP/PS1 mice brain. In addition, DHA treatment increased the level of LC3 II/I and decreased the expression of p62. After Bafilomycin A1 and Chloroquine (CQ) blocked the fusion of autophagy and lysosome, as well as the degradation of autolysosomes (ALs), DHA treatment increased the level of LC3 II/I and decreased the expression of p62. These results suggest that DHA treatment can correct autophagic flux, improve autophagy dysfunction, inhibit abnormal death of neurons, promote the clearance of amyloid-β peptide (Aβ) fibrils, and have a multi-target effect on the neuropathological process, memory and cognitive deficits of AD. [ABSTRACT FROM AUTHOR]