期刊
MOLECULAR PHARMACOLOGY
卷 69, 期 4, 页码 1125-1136出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.105.018408
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资金
- NIA NIH HHS [AG10299] Funding Source: Medline
- NIDDK NIH HHS [DK19645] Funding Source: Medline
- NINDS NIH HHS [NS35107] Funding Source: Medline
Treatment of cells with the macrolide antibiotic bafilomycin A1, an inhibitor of vacuolar (V)-ATPase, or with the lysosomotropic agent chloroquine, has been shown to pharmacologically inhibit autophagy as evidenced by an accumulation of autophagosomes, which in turn causes Bax-dependent apoptosis. However, bafilomycin A1 has also been reported to inhibit chloroquine-induced apoptosis, suggesting a complex interrelationship between these two inhibitors of autophagy. To determine whether the cytoprotective effect of bafilomycin A1 on chloroquine-treated cells was dependent on inhibition of V-ATPase, we examined the single and combined effects of bafilomycin and chloroquine on cultured cerebellar granule neurons. When added separately, chloroquine or high concentrations of bafilomycin A1 (>= 10 nM) induced a dose-dependent inhibition of autophagy (as measured by an increase in LC3-II, a marker specific for autophagosomes), followed by caspase-3 activation and cell death. When added in combination, bafilomycin A1 potently inhibited chloroquine-induced caspase-3 activity and cell death at concentrations (<= 1 nM) that neither altered vacuolar acidification nor inhibited autophagy. The neuroprotective effects of bafilomycin A1 against chloroquine were substantially greater than those produced by Bax deficiency. Bafilomycin A1-induced neuroprotection seemed to be stimulus-specific, in that staurosporine-induced death was not attenuated by coaddition of bafilomycin A1. Together, these data suggest that in addition to promoting death via inhibition of V-ATPase and autophagy, bafilomycin A1 possesses novel, neuroprotective properties that inhibit Bax-dependent activation of the intrinsic apoptotic pathway resulting from the pharmacological inhibition of autophagy.
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