RRC ID 52155
Author Kania E, Pająk B, O'Prey J, Sierra Gonzalez P, Litwiniuk A, Urbańska K, Ryan KM, Orzechowski A.
Title Verapamil treatment induces cytoprotective autophagy by modulating cellular metabolism.
Journal FEBS J
Abstract Verapamil, an L-type calcium channel blocker, has been used successfully to treat cardiovascular diseases. Interestingly, we have recently shown that treatment of cancer cells with verapamil causes an effect on autophagy. As autophagy is known to modulate chemotherapy responses, this prompted us to explore the impact of verapamil on autophagy and cell viability in greater detail. We report here that verapamil causes an induction of autophagic flux in a number or tumor cells and immortalized normal cells. Moreover, we found that inhibition of autophagy in COLO 205 cells, via treatment with the chloroquine (CQ) or by CRISPR/Cas9-mediated disruption of the autophagy genes Atg7 and Atg5, causes an upregulation of apoptotic markers in response to verapamil. In search of a mechanism for this effect and because autophagy can often mitigate metabolic stress, we examined the impact of verapamil on cellular metabolism. This revealed that in normal prostate cells, verapamil diminishes glucose and glycolytic intermediate levels leading to adenosine 5'-triphosphate (ATP) depletion. In contrast, in COLO 205 cells it enhances aerobic glycolysis and maintains ATP. Importantly, we found that the autophagic response in these cells is related to the activity of l-lactate dehydrogenase A (LDHA, EC 1.1.1.27), as inhibition of LDHA reduces both basal and verapamil-induced autophagy and consequently decreases cell viability. In summary, these findings not only identify a novel mechanism of cytoprotective autophagy induction but they also highlight the potential of using verapamil together with inhibitors of autophagy for the treatment of malignant disease. ENZYMES: l-lactate dehydrogenase (LDHA, EC 1.1.1.27).
Volume 284(9)
Pages 1370-1387
Published 2017-5-1
DOI 10.1111/febs.14064
PMID 28342290
MeSH Antimalarials / pharmacology Antineoplastic Agents / adverse effects Antineoplastic Agents / pharmacology* Autophagosomes / drug effects Autophagosomes / metabolism Autophagosomes / ultrastructure Autophagy / drug effects* Autophagy-Related Protein 5 / antagonists & inhibitors Autophagy-Related Protein 5 / genetics Autophagy-Related Protein 5 / metabolism Autophagy-Related Protein 7 / antagonists & inhibitors Autophagy-Related Protein 7 / genetics Autophagy-Related Protein 7 / metabolism Biomarkers / metabolism CRISPR-Cas Systems Calcium Channel Blockers / adverse effects Calcium Channel Blockers / pharmacology* Cell Line, Transformed Cell Line, Tumor Cell Survival / drug effects Cells, Cultured Chloroquine / pharmacology Cytoprotection / drug effects* Energy Metabolism / drug effects Glycolysis / drug effects* Humans Isoenzymes / antagonists & inhibitors Isoenzymes / metabolism L-Lactate Dehydrogenase / antagonists & inhibitors L-Lactate Dehydrogenase / metabolism Lactate Dehydrogenase 5 Microscopy, Electron, Transmission Neoplasms / drug therapy* Neoplasms / metabolism Neoplasms / ultrastructure Verapamil / adverse effects Verapamil / pharmacology*
IF 4.739
Times Cited 12
Resource
Human and Animal Cells KP4(RCB1005)