オートファゴソームに局在するEGFP標識STX17はドキソルビシンによって蓄積する

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  • EGFP-tagged Syntaxin 17 localized on autophagosome is accumulated by Doxorubicin

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<p>Doxorubicin (Dox) is one of the most use and effective anti-cancer regimen. The clinical use of Dox is, however, limited by its cardiotoxicity. Recent studies suggested that Dox exerts cytotoxic effects through impairment of autophagy by unknown mechanisms. Autophagy, an intracellular lysosome-dependent degradation process, is critical for maintaining cellular homeostasis. It involves the formation of autophagosome and its subsequent delivery to lysosome for degradation of sequestrated materials. Syntaxin 17 (STX17), which localized on autophagosome, is known as an essential molecule for the autophagosome-lysosome fusion steps by interacting with soluble SNARE, SNAP29, and the lysosomal SNARE, VAMP8. In this study, we have examined the effect of Dox on the STX17-expression using rat cardiomyoblast H9c2 cells. Western blotting revealed that Dox caused the accumulation of STX17 compared to that without Dox. To further evaluate the effect of Dox on the autophagy flux, we have established the EGFP-tagged STX17 cDNA-expressing H9c2 cells. Dox caused significant augment numbers of EGFP-positive, double-membrane structure which is characteristic of autophagosome, in the cells. Flow cytometric analysis showed that the signal of the EGFP-STX17 was reduced by enhancing the autophagy flux with serum deprivation from the culture medium, whereas, it was increased by addition of Dox to the culture, suggesting that Dox may impede the interaction of STX17 on the autophagosome with SNAP29 and VAMP8 on the lysosome and thus, it augments cardiotoxicity of Dox.</p>

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