Mode of Cell Death Induction by Pharmacological Vacuolar H+-ATPase (V-ATPase) Inhibition

摘要: The vacuolar H+-ATPase (V-ATPase), a multisubunit proton pump, has come into focus as an attractive target in cancer invasion. However, little is known about the role of V-ATPase cell death, and especially underlying mechanisms remain mostly unknown. We used myxobacterial macrolide archazolid B, potent inhibitor V-ATPase, experimental drug well chemical tool to decipher V-ATPase-related death signaling. found that induced apoptosis highly invasive tumor cells at nanomolar concentrations which was executed by mitochondrial pathway. Prior induction led activation cellular stress response including hypoxia-inducible factor-1α (HIF1α) autophagy. Autophagy, demonstrated degradation p62 or fusion autophagosomes with lysosomes, low not yet increase pH lysosomes. HIF1α due energy shown decline ATP level followed shutdown energy-consuming processes. As silencing increases apoptosis, suggested be survival mechanism. conclude leads activates adaptive like autophagy mediated finally apoptosis. propose promising drugable therapy caught up interplay autophagy, cellular/metabolic stress. Background: proposed target, but information on death-inducing rare. Results: Cell involves response. Conclusion: Archazolid Significance: Understanding mechanism inhibition-induced crucial understand impact inhibition treatment.