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Open AccessArticle

Dichloroacetate Affects Mitochondrial Function and Stemness-Associated Properties in Pancreatic Cancer Cell Lines

1
Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture (Pz), Italy
2
Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy
3
Division of Gastroenterology, IRCCS “Casa Sollievo della Sofferenza” Hospital, 71013 San Giovanni Rotondo, Italy
*
Author to whom correspondence should be addressed.
Cells 2019, 8(5), 478; https://doi.org/10.3390/cells8050478
Received: 21 February 2019 / Revised: 14 May 2019 / Accepted: 15 May 2019 / Published: 18 May 2019
(This article belongs to the Special Issue Mitochondrial Bioenergetics in Cancer Cell Biology)
Targeting metabolism represents a possible successful approach to treat cancer. Dichloroacetate (DCA) is a drug known to divert metabolism from anaerobic glycolysis to mitochondrial oxidative phosphorylation by stimulation of PDH. In this study, we investigated the response of two pancreatic cancer cell lines to DCA, in two-dimensional and three-dimension cell cultures, as well as in a mouse model. PANC-1 and BXPC-3 treated with DCA showed a marked decrease in cell proliferation and migration which did not correlate with enhanced apoptosis indicating a cytostatic rather than a cytotoxic effect. Despite PDH activation, DCA treatment resulted in reduced mitochondrial oxygen consumption without affecting glycolysis. Moreover, DCA caused enhancement of ROS production, mtDNA, and of the mitophagy-marker LC3B-II in both cell lines but reduced mitochondrial fusion markers only in BXPC-3. Notably, DCA downregulated the expression of the cancer stem cells markers CD24/CD44/EPCAM only in PANC-1 but inhibited spheroid formation/viability in both cell lines. In a xenograft pancreatic cancer mouse-model DCA treatment resulted in retarding cancer progression. Collectively, our results clearly indicate that the efficacy of DCA in inhibiting cancer growth mechanistically depends on the cell phenotype and on multiple off-target pathways. In this context, the novelty that DCA might affect the cancer stem cell compartment is therapeutically relevant. View Full-Text
Keywords: metabolism; mitochondria; cancer stem cells metabolism; mitochondria; cancer stem cells
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Tataranni, T.; Agriesti, F.; Pacelli, C.; Ruggieri, V.; Laurenzana, I.; Mazzoccoli, C.; Della Sala, G.; Panebianco, C.; Pazienza, V.; Capitanio, N.; Piccoli, C. Dichloroacetate Affects Mitochondrial Function and Stemness-Associated Properties in Pancreatic Cancer Cell Lines. Cells 2019, 8, 478.

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