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Verapamil treatment induces cytoprotective autophagy by modulating cellular metabolism
Author(s) -
Kania Elżbieta,
Pająk Beata,
O'Prey Jim,
Sierra Gonzalez Pablo,
Litwiniuk Anna,
Urbańska Kaja,
Ryan Kevin M.,
Orzechowski Arkadiusz
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14064
Subject(s) - autophagy , verapamil , atg5 , cancer cell , microbiology and biotechnology , biology , glycolysis , pharmacology , viability assay , lactate dehydrogenase , programmed cell death , anaerobic glycolysis , apoptosis , chemistry , cancer research , biochemistry , medicine , cancer , metabolism , calcium , enzyme , genetics
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 ).