DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells.
Although autophagy enhances cell survival in nutrient-deprived cells by increasing adenosine triphosphate (ATP) production, it remains unclear if autophagy functions similarly in cells treated with cytotoxic chemotherapy agents. To address this issue, we measured both the ability of DNA damaging agents (Temozolomide, and Etoposide) to induce an autophagy-dependent production of ATP, and the effects of modulation of autophagy on drug-induced cell death. Both drugs induced an autophagy-associated increase in ATP production in multiple glioma cell lines. The drug-induced ATP surge could not be blocked by glucose starvation, but could be blocked by preincubation with the autophagy inhibitor 3-methyladenine (3-MA), an siRNA targeting beclin 1, or the mitochondrial inhibitor oligomycin. Inhibition of autophagy-induced ATP production increased non-apoptotic cell death associated with micronucleation, while restoration of the 3-MA-inhibited ATP surge by addition of pyruvate suppressed cell death. These results show that DNA damaging agents induce an autophagy-associated ATP surge that protects cells and may contribute to drug resistance.
Katayama
M
M
Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, CA 94115-0875, USA.
Kawaguchi
T
T
Berger
M S
MS
Pieper
R O
RO
D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000502:physiology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D016923:Cell Death; D045744:Cell Line, Tumor; D004249:DNA Damage; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D005047:Etoposide; D003606:Dacarbazine; D000255:Adenosine Triphosphate; D000077204:Temozolomide