DNA fragmentation factor 40 expression in T cells confers sensibility to tributyltin-induced apoptosis

Kulbay, Merve; Johnson, Bruno; Bernier, Jacques

doi:10.1016/j.tox.2019.152255

Cited by 11 publications

(20 citation statements)

References 97 publications

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“…The CRISPR-cas9 system was used to perform gene deletions. Jurkat DFF40 knockout cells were generated as previously described by electroporation [8]. For HeLa cells, DFF40 KO cells were generated by Lipofectamine LTX (Thermo Fisher Scientific Cat# 15338100) transfection using 3x sgRNA/cas9-all-in-one expression plasmids targeting DFF40 gene (GeneCopoeia Cat# HCP256543-CG01-3).…”

Section: Jurkat and Hela Crispr/cas-9 Induced Knockouts Of Dff40mentioning

confidence: 99%

“…Jurkat DFF40 WT and DFF40 KO cells were treated with STS [1 µM] or TBT [0.4 µM] for up to 6 h in RPMI medium supplemented with 0.1% FBS. Following treatments, cell viability was assessed as previously described [8].…”

Section: Cell Viability Assaysmentioning

confidence: 99%

“…DNA fragmentation was evaluated by cell cycle analysis using the G1/G0 subdiploid peak quantification as described previously with some modifications [8]. Briefly, 1 x10 6 DFF40 WT and DFF40 KO Jurkat cells were treated with STS [1 µM] or TBT [0.4 µM] for up to 6 h in RPMI medium supplemented with 0.1% FBS.…”

Section: Apoptosis Assessmentmentioning

confidence: 99%

“…Under expression of DFF40 in uterine leiomyosarcoma's [5], non-endometrioid and high grade endometrioid cancers [6], glioblastoma's and astrocytoma's [7] was shown to be associated with poor prognosis in patients. Recently, our laboratory has shown that knocking out the DFF40 gene in Jurkat cells by CRISPR-cas9 conferred cell resistance to tributyltin (TBT)-induced apoptosis through a delayed activation of the extrinsic apoptotic pathway [8], raising a new hypothesis for its potential novel role in genomic stability [9]. Mitochondria of cancer cells are known to be one of the most crucial bio cellular features in malignant tumor progression, by the regulation of mitochondrial DNA (mtDNA) and cell metabolism [10].…”

Section: Introductionmentioning

confidence: 99%

“…It is known that disruption of CIDE domains can cause metabolic disorders (e.g., diabetes, obesity, cardiovascular diseases) [15] and the alteration of their expression by gene deletion can be related to cancer development [5,7]. Our laboratory recently demonstrated that DFF40 deficiency in Jurkat T cells induced a higher redox state at basal state [8]. Recently, it was shown that elevated ROS production in cancer cells was associated with higher mtDNA copy number (mtDNAcn) [19].…”

Section: Introductionmentioning

confidence: 99%

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Energetic metabolic reprogramming in Jurkat DFF40-deficient cancer cells

et al. 2022

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DNA fragmentation factor 40 (DFF40), or the caspase-activated DNase (CAD), is an endonuclease specific for double-stranded DNA. Alterations in its function and expression have been linked to apoptosis resistance, a mechanism likely used by cancer cells.Although, how the DFF40-related apoptosis resistance pathway occurs remains unclear.Here we sought to determine if DFF40 expression could be linked to cell metabolism through the regulation of mitochondrial integrity and function. We demonstrated that DFF40 deficient cells are more resistant to staurosporine (STS) and tributyltin (TBT)induced apoptosis, and express higher levels of Mcl-1 at basal state. Treatment with TBT induces higher Bcl-2 and caspase-9 mRNA transcripts in DFF40 KO Jurkat cells, as well as enhanced Bcl-2 phosphorylation. A loss of DFF40 expression induces a higher mitochondrial mass, mtDNA copy number, mitochondrial membrane potential and glycolysis rates in resting T cells. DFF40 deficient cells exhibit the Warburg effect phenotype, where they rely significantly more on glycolysis and have a higher proliferative state, demonstrated by a higher Ki-67 transcription factor expression and AKT phosphorylation. Finally, we demonstrated with cell fractioning that DFF40 can translocate to the mitochondria following apoptosis induction. Our study reveals that DFF40 may act as a regulator of mitochondria during cell death, and its loss could compromise mitochondrial integrity and cause an energetic reprogramming in pathologies such as cancer.

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Section: Jurkat and Hela Crispr/cas-9 Induced Knockouts Of Dff40mentioning

confidence: 99%

Section: Cell Viability Assaysmentioning

confidence: 99%

Section: Apoptosis Assessmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Energetic metabolic reprogramming in Jurkat DFF40-deficient cancer cells

et al. 2022

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Review of cancer cell resistance mechanisms to apoptosis and actual targeted therapies

Kulbay

Paimboeuf

Ozdemir

et al. 2021

J of Cellular Biochemistry

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The apoptosis pathway is a programmed cell death mechanism that is crucial for cellular and tissue homeostasis and organ development. There are three major caspase‐dependent pathways of apoptosis that ultimately lead to DNA fragmentation. Cancerous cells are known to highly regulate the apoptotic pathway and its role in cancer hallmark acquisition has been discussed over the past decades. Numerous mutations in cancer cell types have been reported to be implicated in chemoresistance and treatment outcome. In this review, we summarize the mutations of the caspase‐dependant apoptotic pathways that are the source of cancer development and the targeted therapies currently available or in trial.

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