Pyruvate dehydrogenase kinase expression and metabolic changes following dichloroacetate exposure in anoxic human colorectal cancer cells

Ho, Nelson; Coomber, Brenda L.

doi:10.1016/j.yexcr.2014.12.006

Cited by 29 publications

(24 citation statements)

References 30 publications

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“…This finding is in accordance with previous results presented by bonnet et al in several human cell lines (35) and Sun et al in breast cancer (12). Further, decreased cell proliferation after DCA exposure was also observed in human prostate carcinoma (36), colorectal (37), colon (11) and lung cancer (38). However, induction of mitochondria dependent apoptosis by DCA, as previously reported by several research groups (14,35,39) could not be observed in this study.…”

Section: Discussionsupporting

confidence: 93%

The effect of dichloroacetate in canine prostate adenocarcinomas and transitional cell carcinomas in vitro

Harting

Stubbendorff

Willenbrock

et al. 2016

International Journal of Oncology

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The Warburg effect describes the ability of cancer cells to produce energy via aerobic glycolysis instead of oxidative phosphorylation of pyruvate. This deviation in mitochondrial metabolism inhibits apoptosis, allowing increased proliferation under conditions of reduced oxygen levels. Dichloroacetate (DCA) was successfully used in several human cancer cell lines to reactivate oxidative phosphorylation in mitochondria. The aim of this study was the characterization and response of canine cancer cell lines after DCA exposure. The effect of 10 mM DCA was characterized in vitro on a set of six canine prostate adenocarcinoma and transitional cell carcinoma (TCC) derived cell lines. Cell counts, lactate levels, apoptosis, expression of apoptotic proteins, survival factors and different miRNAs were analyzed. Additionally, metabolic activity, mitochondrial activity and proliferation were investigated. DCA significantly decreased cell number of all but one utilized cell lines and leads to a significant reduction of lactate release. Decreased survivin levels were found in all cell lines, two of which presented a significant reduction in metabolic activity. Increased miR-375 levels were measured in all TCC cell lines. Reactivation of pyruvate dehydrogenase and an elevated mitochondrial activity appear to induce the transition from aerobic glycolysis back to oxidative phosphorylation. Further, these results display that DCA treatment has a suppressant effect on proliferation of canine cancer cells.

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Section: Discussionsupporting

confidence: 93%

The effect of dichloroacetate in canine prostate adenocarcinomas and transitional cell carcinomas in vitro

Harting

Stubbendorff

Willenbrock

et al. 2016

International Journal of Oncology

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“…This supports the assumption of Rardin et al, that PDH phosphorylation at Ser 232 is not limited to heart tissue [44]. In contrast to studies in humans, Ser 293 phosphorylation was not significantly affected by DCA [29, 30]. Ser 293 is reported to be phosphorylated rapidly by PDK, especially isoform 2 [44], indicating that DCA might not influence all PDK isoforms equally in dogs.…”

Section: Discussionsupporting

confidence: 84%

Dichloroacetate affects proliferation but not apoptosis in canine mammary cell lines

et al. 2017

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Targeting mitochondrial energy metabolism is a novel approach in cancer research and can be traced back to the description of the Warburg effect. Dichloroacetate, a controversially discussed subject of many studies in cancer research, is a pyruvate dehydrogenase kinase inhibitor. Dichloroacetate causes metabolic changes in cancerous glycolysis towards oxidative phosphorylation via indirect activation of pyruvate dehydrogenase in mitochondria. Canine mammary cancer is frequently diagnosed but after therapy prognosis still remains poor. In this study, canine mammary carcinoma, adenoma and non-neoplastic mammary gland cell lines were treated using 10 mM Dichloroacetate. The effect on cell number, lactate release and PDH expression and cell respiration was investigated. Further, the effect on apoptosis and several apoptotic proteins, proliferation, and microRNA expression was evaluated. Dichloroacetate was found to reduce cell proliferation without inducing apoptosis in all examined cell lines.

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“…Meanwhile, when comparing the TT with the pNT, the current study found an increased expression of PDK1, a critical enzyme in the tricarboxylic acid cycle for cellular respiration. This agrees with a previous study of PDK expression in anoxic human colorectal cancer cells, which suggested that human colon cancer cell lines highly expressed PDK1 and 3, while isoforms 2 and 4 were not highly expressed [11]. PDK1 expression has also been proposed as a poor prognostic factor for patients with gastric cancer [12].…”

Section: Discussionsupporting

confidence: 91%

Clinical Implication of Serine Metabolism-Associated Enzymes in Colon Cancer

Yoon

Kim

Seo³

et al. 2015

Oncology

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Purpose: Recently, enzymes of the serine synthetic pathway (SSP) have been suggested as key player in the metabolic adaptation of oncogenesis. We assessed the expression of enzymes of the SSP in colonic tumor tissue (TT) and paired normal tissue (pNT) and the prognostic implications. Methods: From 2006 to 2010, we included 486 patients with colon cancer who underwent curative surgery at Kyungpook National University Hospital. Phosphoglycerate dehydrogenase (PHGDH), pyruvate dehydrogenase kinase (PDK) 1, PDK2, pyruvate kinase M2 (PKM2), and phosphoserine aminotransferase (PSAT) expression were investigated by immunohistochemical staining (IHC) in TT and pNT. The IHC values were calculated by multiplying intensity by proportion. The final score was classified as follows: 0-2 as negative and 3-12 as positive. Results: During the median follow-up duration of 55.5 months (37.4-90.6), 78 patients experienced recurrence. The expression of PHGDH, PDK1, and PSAT was significantly higher in TT than pNT (p < 0.001 for each). The univariate analysis for relapse-free survival revealed that TT PDK2 positivity was the only positive prognostic factor (p = 0.023). However, the expression of TT PDK2 did not represent a prognostic value in multivariate analysis. Conclusions: In conclusion, PHGDH, PDK1, and PSAT were significantly increased in colonic TT compared with pNT. The prognostic implication of these enzymes needs to be further investigated.

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Pyruvate dehydrogenase kinase expression and metabolic changes following dichloroacetate exposure in anoxic human colorectal cancer cells

Cited by 29 publications

References 30 publications

The effect of dichloroacetate in canine prostate adenocarcinomas and transitional cell carcinomas in vitro

The effect of dichloroacetate in canine prostate adenocarcinomas and transitional cell carcinomas in vitro

Dichloroacetate affects proliferation but not apoptosis in canine mammary cell lines

Clinical Implication of Serine Metabolism-Associated Enzymes in Colon Cancer

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