The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway

Khan, Asaad; Allende-Vega, Nerea; Gitenay, Delphine; Gerbal‐Chaloin, Sabine; Gondeau, Claire; Vo, Dang Nghiem; Belkahla, Sana; Orecchioni, Stefania; Talarico, Giovanna; Bertolini, Francesco; Božić, Milica; Valdivielso, José M.; Bejjani, Fabienne; Jariel, Isabelle; López-Mejía, Isabel C.; Fajas, Lluís; Lecellier, Charles-Henri; Hernandez, Javier; Daujat, Martine; Villalba, Martín

doi:10.1038/s41598-017-10339-5

Cited by 26 publications

(42 citation statements)

References 45 publications

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“…Little to nothing is known about lipid metabolism in SCLC and the connection between the MEK5-ERK5 axis and lipid homeostasis (29,30). Consistent with our findings, one of the most significant transcription factor target gene sets to be identified by GSEA as disenriched in MEK5 and ERK5-deficient cells, was SREBP (Sterol-Regulatory Element Binding Protein) target genes ( Supplementary Fig.…”

Section: Mek5 and Erk5 Knockdown Affects Cholesterol Synthesis Pathwayssupporting

confidence: 86%

“…Emerging evidence also links MEK5 and ERK5 to the control of oxidative phosphorylation (39). Notably, one study makes a connection between forced oxidative phosphorylation and downstream effects on cholesterol levels, via an increase in LDLR expression and intracellular LDL-cholesterol intake-a process dependent on the MEK5-ERK5 axis (29). To our knowledge, however, there is no prior direct description of a control of de novo cholesterol synthesis by the MEK5-ERK5 axis.…”

Section: Discussionmentioning

confidence: 99%

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The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

et al. 2020

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Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few kinases known to promote the development of SCLC. Here, we investigated the contribution of the MAPK module MEK5-ERK5 to SCLC growth. MEK5 and ERK5 were required for optimal survival and expansion of SCLC cell lines in vitro and in vivo. Transcriptomics analyses identified a role for the MEK5-ERK5 axis in the metabolism of SCLC cells, including lipid metabolism. In-depth lipidomics analyses showed that loss of MEK5/ERK5 perturbs several lipid metabolism pathways, including the mevalonate pathway that controls cholesterol synthesis. Notably, depletion of MEK5/ERK5 sensitized SCLC cells to pharmacologic inhibition of the mevalonate pathway by statins. These data identify a new MEK5-ERK5-lipid metabolism axis that promotes the growth of SCLC. Significance: This study is the first to investigate MEK5 and ERK5 in SCLC, linking the activity of these two kinases to the control of cell survival and lipid metabolism.

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Section: Mek5 and Erk5 Knockdown Affects Cholesterol Synthesis Pathwayssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

et al. 2020

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“…OCI-AML3, but not all, e.g. Jurkat 11 , 27 , 29 . In contrast, both cell lines increased NRF2 expression suggesting that ROS production was not essential for this induction (Fig.…”

Section: Resultsmentioning

confidence: 95%

Mitochondrial Complex I activity signals antioxidant response through ERK5

Khan

Allende-Vega

Gitenay

et al. 2018

Sci Rep

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Oxidative phosphorylation (OXPHOS) generates ROS as a byproduct of mitochondrial complex I activity. ROS-detoxifying enzymes are made available through the activation of their antioxidant response elements (ARE) in their gene promoters. NRF2 binds to AREs and induces this anti-oxidant response. We show that cells from multiple origins performing OXPHOS induced NRF2 expression and its transcriptional activity. The NRF2 promoter contains MEF2 binding sites and the MAPK ERK5 induced MEF2-dependent NRF2 expression. Blocking OXPHOS in a mouse model decreased Erk5 and Nrf2 expression. Furthermore, fibroblasts derived from patients with mitochondrial disorders also showed low expression of ERK5 and NRF2 mRNAs. Notably, in cells lacking functional mitochondrial complex I activity OXPHOS did not induce ERK5 expression and failed to generate this anti-oxidant response. Complex I activity induces ERK5 expression through fumarate accumulation. Eukaryotic cells have evolved a genetic program to prevent oxidative stress directly linked to OXPHOS and not requiring ROS.

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“…ABCB1 and ABCC1, have MEF2A binding sites. MEF2 mediates a large part of the observed ERK5 effects on metabolism [ 15 , 16 , 47 ]. Hence, this could also be the case of ABC transporters.…”

Section: Discussionmentioning

confidence: 99%

“…The expression vectors for ERK5, the pSUPER expression vector for GFP alone or GFP plus shERK5 have been previously described [ 46 ]. Control, ERK5 and p53 siRNA were ON-TARGETplus SMARTpools (mixture of 4 siRNA) from Dharmacon and has been previously used [ 7 , 47 ]. ERK5 shRNA (AGCTGCCCTGCTCAAGTCT) was transfected in Jurkat cells as previously described [ 46 ].…”

Section: Methodsmentioning

confidence: 99%

Changes in metabolism affect expression of ABC transporters through ERK5 and depending on p53 status

et al. 2017

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Changes in metabolism require the efflux and influx of a diverse variety of metabolites. The ABC superfamily of transporters regulates the exchange of hundreds of substrates through the impermeable cell membrane. We show here that a metabolic switch to oxidative phosphorylation (OXPHOS), either by treating cells with dichloroacetate (DCA) or by changing the available substrates, reduced expression of ABCB1, ABCC1, ABCC5 and ABCG2 in wild-type p53-expressing cells. This metabolic change reduced histone changes associated to active promoters. Notably, DCA also inhibited expression of these genes in two animal models in vivo. In contrast, OXPHOS increased the expression of the same transporters in mutated (mut) or null p53-expressing cells. ABC transporters control the export of drugs from cancer cells and render tumors resistant to chemotherapy, playing an important role in multiple drug resistance (MDR). Wtp53 cells forced to perform OXPHOS showed impaired drug clearance. In contrast mutp53 cells increased drug clearance when performing OXPHOS. ABC transporter promoters contain binding sites for the transcription factors MEF2, NRF1 and NRF2 that are targets of the MAPK ERK5. OXPHOS induced expression of the MAPK ERK5. Decreasing ERK5 levels in wtp53 cells increased ABC expression whereas it inhibited expression in mutp53 cells. Our results showed that the ERK5/MEF2 pathway controlled ABC expression depending on p53 status.

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The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway

Cited by 26 publications

References 45 publications

The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

The MEK5–ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer

Mitochondrial Complex I activity signals antioxidant response through ERK5

Changes in metabolism affect expression of ABC transporters through ERK5 and depending on p53 status

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