Evidence supporting a role for dihydroorotate dehydrogenase, bioenergetics, and p53 in selective teriflunomide-induced apoptosis in transformed versus normal human keratinocytes

Hail, Numsen; Chen, Ping; Kepa, Jadwiga J.; Bushman, Lane R.

doi:10.1007/s10495-011-0667-0

Cited by 24 publications

(21 citation statements)

References 36 publications

(67 reference statements)

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“…The results are in good agreement with data indicating that the DHODH inhibitor leflunomide/teriflunomide induces apoptosis in a number of human cancer cell lines [10-12]. However, according to [12], transformed keratinocytes with the mutant p53 gene, which lack transcriptionally active p53, are more sensitive to apoptosis induced by teriflunomide than normal keratinocytes with wild-type p53.…”

Section: Discussionsupporting

confidence: 86%

“…However, according to [12], transformed keratinocytes with the mutant p53 gene, which lack transcriptionally active p53, are more sensitive to apoptosis induced by teriflunomide than normal keratinocytes with wild-type p53. In normal human epidermal keratinocytes (NHEK) a long-term exposure to teriflunomide was shown to induce cell cycle arrest at Go/G1 due to an induction of the p53 regulated gene CDKN1A encoding the cyclin-dependent kinase inhibitor p21.…”

Section: Discussionmentioning

confidence: 99%

“…In normal human epidermal keratinocytes (NHEK) a long-term exposure to teriflunomide was shown to induce cell cycle arrest at Go/G1 due to an induction of the p53 regulated gene CDKN1A encoding the cyclin-dependent kinase inhibitor p21. The response apparently reflects a cytoprotective role for p53 against teriflunomide-induced apoptosis [12]. Treatment of human fibroblasts with PALA, another inhibitor of pyrimidine biosynthesis (N-phosphonacetyl- L-aspartate, transcarbamylase inhibitor), led to reversible cell cycle arrest, survival of cells expressing transcriptionally active p53, and apoptotic cell death in the absence of p53 [13-15].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III

et al. 2014

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A mechanism for the induction of programmed cell death (apoptosis) upon dysfunction of the mitochondrial respiratory chain has been studied. Previously, we had found that inhibition of mitochondrial cytochrome bc1, a component of the electron transport chain complex III, leads to activation of tumor suppressor p53, followed by apoptosis induction. The mitochondrial respiratory chain is coupled to the de novo pyrimidine biosynthesis pathway via the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). The p53 activation induced in response to the inhibition of the electron transport chain complex III has been shown to be triggered by the impairment of the de novo pyrimidine biosynthesis due to the suppression of DHODH. However, it remained unclear whether the suppression of the DHODH function is the main cause of the observed apoptotic cell death. Here, we show that apoptosis in human colon carcinoma cells induced by the mitochondrial respiratory chain complex III inhibition can be prevented by supplementation with uridine or orotate (products of the reaction catalyzed by DHODH) rather than with dihydroorotate (a DHODH substrate). We conclude that apoptosis is induced in response to the impairment of the de novo pyrimidine biosynthesis caused by the inhibition of DHODH. The conclusion is supported by the experiment showing that downregulation of DHODH by RNA interference leads to accumulation of the p53 tumor suppressor and to apoptotic cell death.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III

et al. 2014

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“…Interestingly, the inhibitors of DHODH are currently used for the therapy of autoimmune diseases, and celastrol has long been proved to be very effective for this kind of disease [40]. Furthermore, it was reported that the inhibition of DHODH could induce apoptosis [41–43]. Teriflunomide, a well-known specific inhibitor of DHODH, could also induce significant apoptosis of APL cells in our study (Figure 6).…”

Section: Discussionsupporting

confidence: 61%

Metabolomics profiles delineate uridine deficiency contributes to mitochondria-mediated apoptosis induced by celastrol in human acute promyelocytic leukemia cells

Yang

Chen

et al. 2016

Oncotarget

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Celastrol, extracted from “Thunder of God Vine”, is a promising anti-cancer natural product. However, its effect on acute promyelocytic leukemia (APL) and underlying molecular mechanism are poorly understood. The purpose of this study was to explore its effect on APL and underlying mechanism based on metabolomics. Firstly, multiple assays indicated that celastrol could induce apoptosis of APL cells via p53-activated mitochondrial pathway. Secondly, unbiased metabolomics revealed that uridine was the most notable changed metabolite. Further study verified that uridine could reverse the apoptosis induced by celastrol. The decreased uridine was caused by suppressing the expression of gene encoding Dihydroorotate dehydrogenase, whose inhibitor could also induce apoptosis of APL cells. At last, mouse model confirmed that celastrol inhibited tumor growth through enhanced apoptosis. Celastrol could also decrease uridine and DHODH protein level in tumor tissues. Our in vivo study also indicated that celastrol had no systemic toxicity at pharmacological dose (2 mg/kg, i.p., 21 days). Altogether, our metabolomics study firstly reveals that uridine deficiency contributes to mitochondrial apoptosis induced by celastrol in APL cells. Celastrol shows great potential for the treatment of APL.

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“…The proapoptotic effect of teriflunomide involves oxidative stress, mitochondrial depolarization and caspase activation [22,23].…”

Section: Introductionmentioning

confidence: 99%

Inhibition by Teriflunomide of Erythrocyte Cell Membrane Scrambling Following Energy Depletion, Oxidative Stress and Ionomycin

Zierle

Bissinger²,

Läng

2016

Cell Physiol Biochem

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Background/Aims: Teriflunomide, an inhibitor of pyrimidine synthesis and thus proliferation of activated T and B lymphocytes, is successfully used for treatment of inflammatory disease. Teriflunomide has further been shown to trigger apoptosis of tumor cells and has thus been considered for the treatment of malignancy. In analogy to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and phospholipid scrambling of the cell membrane with translocation of phosphatidylserine to the erythrocyte surface. Triggers of cell membrane scrambling include energy depletion, oxidative stress and increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i). The present study explored whether teriflunomide modifies eryptosis. Methods: Flow cytometry was employed to estimate phosphatidylserine abundance at the erythrocyte surface from annexin-V-binding, cell volume from forward scatter, and [Ca²⁺]_i from Fluo3 fluorescence. Results: Oxidative stress (60 min exposure to 0.3 mM tert-butylhydroperoxide), energy depletion (removal of glucose for 48 hours), and exposure to the Ca²⁺ ionophore ionomycin (1 µM, 60 min) all increased annexin-V-binding, decreased forward scatter and enhanced Fluo3 fluorescence. Teriflunomide (5 µg/ml) did not significantly influence Fluo3 fluorescence, forward scatter and annexin-V-binding under control conditions but significantly blunted the increase of annexin-V-binding following oxidative stress, energy depletion and ionomycin exposure. Teriflunomide further blunted the increase of Fluo3 fluorescence following energy depletion, but did not significantly interfere with increase of Fluo3 fluorescence following oxidative stress and ionomycin exposure. Conclusion: Teriflunomide is a novel inhibitor of suicidal erythrocyte death.

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Evidence supporting a role for dihydroorotate dehydrogenase, bioenergetics, and p53 in selective teriflunomide-induced apoptosis in transformed versus normal human keratinocytes

Cited by 24 publications

References 36 publications

The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III

The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III

Metabolomics profiles delineate uridine deficiency contributes to mitochondria-mediated apoptosis induced by celastrol in human acute promyelocytic leukemia cells

Inhibition by Teriflunomide of Erythrocyte Cell Membrane Scrambling Following Energy Depletion, Oxidative Stress and Ionomycin

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