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Long-term 1,2-dimethylhydrazine triggers pathological remodeling of colon mucosa through repression of sestrin2, nuclear factor (erythroid-derived 2)-like 2, and sirtuin4 stimulating mitochondrial stress and metabolic reprogramming

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Abstract

1,2-Dimethylhydrazine (DMH) is a plant toxicant that enters the food web through the diet. It is biotransformed into azoxymethane, a colon carcinogen, during the first hepatic passage. In mice, this study assessed the role of glutamate dehydrogenase (GDH), a key glutaminolysis enzyme in DMH-induced colorectal cancer (CRC). Colon samples were taken from mice given 6 or 15 weekly doses of 20 mg/kg DMH and serially sacrificed. Repeated DMH doses induced early aberrant crypt foci that evolved into irreversible adenocarcinomas over 24 weeks, along with an increase in GDH and lactate dehydrogenase activities (+ 122%, + 238%, P < 0.001), indicating a switch to aerobic glycolysis and glutaminolysis. Transcriptional downregulation of the endogenous GDH inhibitor, sirtuin4, and two redox regulators, mitochondrial sestrin2 and nuclear factor (erythroid derivative 2)-like 2 (− 26% and − 22%, P < 0, 05; and − 30%, P < 0.01), exacerbated mitochondrial stress by boosting mitochondrial superoxide dismutase activity (+ 240% (P < 0.001) while depressing catalase activity and GSH levels (− 57% and − 60%, P < 0.001). In vitro, allosteric GDH inhibition by 50 µM epigallocatechin gallate decreased human carcinoma (HCT-116) cells’ viability, clonogenicity, and migration (− 43% and − 57%, P < 0.001, 41%, P < 0.05), while stimulating ROS release (+ 57%, P < 0.001). Dimethylfumarate (DMF), a linear electrophile and mitochondrial fumarate analog, rebalanced ROS levels (− 34%, P < 0.05) and improved GDH activity, cell viability, and tumorogenic capacity (+ 20%, 20%, P < 0.001; and 33%, P < 0.05). Thus, the pathological remodeling of colon mucosa is supported by metabolic reprogramming bypassing uncoupled mitochondria. DMF highlights the critical role of electrophile response elements in modulating redox mithormesis and redox homeostasis during CRC.

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Data availability

All histological, immunochemical, biochemical, and RT-PCR data are available upon request from the first author.

Abbreviations

AOM:

Azoxymethane

BCH:

2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid

DMF:

Dimethylfumarate

DMH:

1,2-Dimethylhydrazine

E-Cad:

E-cadherin

EGCG:

Epigallocatechin gallate

Ep/ARE:

Electrophile/antioxidants response elements

GDH:

Glutamate dehydrogenase

GSH:

Reduced glutathione

GLUT:

Glucose transporter

MDZ:

Methyldiazonium

MAM:

Methylcarbabonium

CH3+ :

Methyl cation

MnSOD:

Manganese superoxide dismutase

mtROS:

Mitochondrial reactive oxygen species

mtO2 − :

Mitochondrial superoxide anion

NAC:

N-acetylcysteine

Nrf2:

Nuclear factor (erythroid-derived 2)-like 2

PTEN:

Phosphatase and tensin homolog

ROS:

Reactive oxygen species

Sesn2:

Sestrin2

Sirt4:

Sirtuin4

α-SMA:

α-Smooth muscle actin

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Acknowledgements

We acknowledge all the staff of the Laboratory of Pharmacology (University of Porto, Portugal) for their valuable scientific contribution to this study.

This study was supported in part by the “Direction Générale de la Recherche Scientifique et du Development Technique (DG-RSDT),” Algiers, Algeria.

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Authors and Affiliations

  1. Tamayouz_Laboratory of Cellular and Molecular Biology, University of Sciences and Technology Houari Boumediene, Algiers, Algeria

    Bader-Edine Allal, Abdelkader Bounaama & Bahia Djerdjouri

  2. Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacia, University of Porto, Porto, Portugal

    Bader-Edine Allal, Dany Silva, Clara Quintas & Jorge Gonçalves

  3. Department of Anatomopathology, Central Hospital of Army, Algiers, Algeria

    Salim Ismail Dahlouk

Authors
  1. Bader-Edine Allal
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  2. Abdelkader Bounaama
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  3. Dany Silva
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  4. Clara Quintas
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  5. Salim Ismail Dahlouk
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  6. Jorge Gonçalves
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  7. Bahia Djerdjouri
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Contributions

BD, JG, and BA designed the research. AB contributed to the experimental tumorigenesis protocol. BA, DS, and CQ conducted experiments. SYD made the histological and immunohistological evaluations. BD, JG, and BA analyzed data and wrote the manuscript. BD revised the manuscript.

Corresponding author

Correspondence to Bahia Djerdjouri.

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Ethical approval

All the in vivo experiments were carried out in agreement with the Ethics Committee for Animal Welfare of the University of Science and Technology Houari Boumediene (Algiers) [Algerian Law 12–235/2012; Executive Decree No. 10–90] and in accordance with the European Directive 2010/63/EU for ethics in animal experimentation.

Consent to participate and for publication

All authors consent to participate in this study. They read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Not applicable.

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Highlights

• 1,2-Dimethylhydrazine (DMH) depresses Sesn2 and Nrf2 and redox homeostasis.

• Long-term DMH supports glutamate dehydrogenase (GDH) activity by blocking sirtuin4.

• the burst in matrix superoxide dismutase activity induced mitochondrial stress.

• Dimethylfumarate (DMF) rescued GDH activity inhibited by epigallocatechin gallate.

• DMF triggers GDH-mediated cancer cell's viability, motility and clogenicity.

Supplementary Information

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Supplementary file1 (PDF 269 KB)

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Allal, BE., Bounaama, A., Silva, D. et al. Long-term 1,2-dimethylhydrazine triggers pathological remodeling of colon mucosa through repression of sestrin2, nuclear factor (erythroid-derived 2)-like 2, and sirtuin4 stimulating mitochondrial stress and metabolic reprogramming. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1291–1307 (2023). https://doi.org/10.1007/s00210-023-02403-x

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