Dendritic cells (DCs) play an important role in initiating antitumour immune response. Tumour progression usually induces defects in DC maturation and thus tumour-bearing hosts exhibit immunosuppression and tumour escape. The previous studies showed that an exopolysaccharide (EPS) from a fungus, one anamorph of Cordyceps sinensis, inhibited tumour growth via activating immune response in the hosts. In view of the crucial actions of DCs in antitumour immunity, the present study aims to explore the effects of EPS on murine DCs. Murine DCs were derived from the bone marrow of C57BL/6 mice, and the effects of EPS on phenotype molecules and ingestion function of DCs were assayed using flow cytometry. Cytokine expressions of DCs were assayed by reverse transcriptase-PCR. Additionally, the level of phosphorylated signal transducers and activators of transcription 3 (p-STAT3) of DCs was evaluated using Western blotting. The results showed that EPS promoted the levels of surface molecules MHC II, CD40, CD80 and CD86 of DCs and decreased their ingestion ability. The mRNA expressions of cytokines (IL-12p40 and TNF-α) and inducible nitric oxide synthase were up-regulated by EPS. We also found that EPS significantly down-regulated p-STAT3 level of DCs. The results suggested that the promotion of DC's maturation and activation by EPS is probably related to the inhibition of STAT3 phosphorylation.
The mechanisms of cancer cell adaptation to tumor microenvironmental conditions, such as hypoxia and nutrient starvation, are currently receiving much attention as possible therapeutic targets. In an attempt to identify selectively cytotoxic substances against cancer cells adapted to nutrient starvation, 4 abietane-type diterpenes, sugiol (1), 6-α-hydroxysugiol (2), cryptojaponol (3), and 6-hydroxy-5,6-dehydrosugiol (4), were isolated from the bark of Taxodium distichum L. Rich var. distichum (bald cypress). Compounds 1, 2, and 4 showed potent cytotoxic activity against PANC-1 cells adapted to nutrient-starved conditions with half-maximal effective concentration (EC50) values of 6.4-9.2 µM, whereas the EC50 values of these compounds against PANC-1 cells under general culture conditions were more than 100 µM. Alternatively, compound 3, which we report for the first time in the genus Taxodium, showed moderate cytotoxicity against PANC-1 cells under nutrient-starved conditions with an EC50 of 37.9 µM. The selective index (S.I.), which compared the activity under nutrient-starved conditions with that under general culture conditions, was low (7.9). Further investigation revealed that the selective cytotoxic activity of compound 2 might be affecting the mitochondria.
Cancer cells secrete aberrantly large amounts of extracellular vesicles (EVs) including exosomes, which originate from multivesicular bodies (MVBs). Because EVs potentially contribute to tumor progression, EV inhibitors are of interest as novel therapeutics. We screened a fungal natural product library. Using cancer cells engineered to secrete luciferase-labeled EVs, we identified asteltoxin, which inhibits mitochondrial ATP synthase, as an EV inhibitor. Low concentrations of asteltoxin inhibited EV secretion without inducing mitochondrial damage. Asteltoxin attenuated cellular ATP levels and induced AMPK-mediated mTORC1 inactivation. Consequently, MiT/TFE transcription factors are translocated into the nucleus, promoting transcription of lysosomal genes and lysosome activation. Electron microscopy analysis revealed that the number of lysosomes increased relative to that of MVBs and the level of EVs decreased after treatment with asteltoxin or rapamycin, an mTORC1 inhibitor. These findings suggest that asteltoxin represents a new type of EV inhibitor that controls MVB fate.
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