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Transient receptor potential channel stimulation induced oxidative stress and apoptosis in the colon of mice with colitis-associated colon cancer: modulator role of Sambucus ebulus L.

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Abstract

Background

Increased Ca2+ entry causes an increase in tumor cell proliferation, apoptosis, cytosolic reactive free oxygen species (cyROS), and mitochondrial ROS (miROS) in tumor cells. The cyROS and miROS stimulate the cation channels, including the TRPA1, TRPM2, and TRPV1. Sambucus ebulus L (SEB) (Dwarf Elder) induced both antioxidant and anticancer effects in the human hepatocarcinoma and human colon carcinoma cancer cell lines. We investigated the etiology of colorectal cancer and the impact of three channels, as well as the protective effects of SEB on apoptosis, cyROS, and miROS in the colon of mice with colitis-associated colon cancer (AOM/DSS).

Methods

A total 28 mice were equally divided into four groups as control, SEB (100 mg/kg/day for 14 days), AOM/DSS, and SEB + AOM/DSS. Azoxymethane/dextran sulfate sodium-induced colon cancer associated with colitis was induced in the AOM/DSS groups within 10 weeks. At the end of the experiments, the colon samples were removed from the mice.

Results

The protein bands of caspase − 3, TRPA1, TRPM2, and TRPV1 were increased by the treatments of AOM/DSS. The levels of apoptosis, cyROS, cleaved caspase − 3, and cleaved caspase − 9, as well as the depolarization of the mitochondrial membrane, all increased in the AOM/DSS group. Although they were reduced in the SEB and AOM/DSS + SEB groups by the treatments of SEB, TRPA1 (AP18), TRPM2 (ACA), and TRPV1 (capsazepine) antagonists, the apoptotic and oxidant values were further elevated in the AOM/DSS group by the treatments of TRPA1 (cinnamaldehyde), TRPM2 (H2O2), and TRPV1 (capsaicin) agonists.

Conclusion

The activations of TRPA1, TRPM2, and TRPV1 channels induced the increase of apoptotic and oxidant actions in the colon cancer cells, although their inhibition via SEB treatment decreased the actions. Hence, TRPA1, TRPM2, and TRPV1 activations could be used as effective agents in the treatment of colon tumors.

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Data availability

The data used to support the findings of present study are available from the corresponding author upon request.

Abbreviations

ACA:

N-(p-amylcinnamoyl)anthranilic acid

ADPR:

ADP-ribose

Ca2+ :

Calcium ion

CAP:

Capsaicin

CASP/3:

Cleaved caspase − 3

CASP/9:

Cleaved caspase − 9

CiNN:

Cinnamaldehyde

CPZ:

Capsazepine

cyROS:

Cytosolic reactive oxygen species

miPOT:

Mitochondrial membrane potential

miROS:

Mitochondrial reactive oxygen species

TRP:

Transient receptor potential

TRPA1:

Transient receptor ankyrin 1

TRPM2:

Transient receptor potential melastatin 2

TRPV1:

Transient receptor potential vanilloid 1

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Acknowledgements

The antioxidant and cleaved caspase analyses in the current study were performed in 7th International Brain Research School, 27 June and 3 July 2022, Isparta, Türkiye by Dr. Müge Mavioğlu Kaya. (http://2022.brs.org.tr/). The remaining analyses were performed by Prof. Dr. M Nazıroğlu and technicians (Fatih Şahin and Muhammet Şahin- BSN Health Analyses Ltd., Isparta, Türkiye).

Funding

The study was supported by Scientific Unit of Kafkas University (BAP), Kars, Türkiye (Project No: 2022-FM-14. Project owner: Assist. Prof. Dr. Müge Mavioğlu Kaya). There is no financial disclosure in the current study.

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Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Faculty of Science, Kafkas University, 36100, Kars, Turkey

    Müge Mavioğlu Kaya

  2. Department of Biology, Faculty of Science, Kafkas University, 36100, Kars, Turkey

    İnan Kaya

  3. Neuroscience Research Center, Suleyman Demirel University, 32260, Isparta, Turkey

    Mustafa Nazıroğlu

  4. BSN Health, Analysis and Innovation Ltd, Türkiye, 32260, Isparta, Turkey

    Mustafa Nazıroğlu

  5. Department of Biophysics Faculty of Medicine, Suleyman Demirel University, 32260, Isparta, Türkiye

    Mustafa Nazıroğlu

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  1. Müge Mavioğlu Kaya
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Contributions

MMK: Animal experiments, Methodology, Formal analysis, Data curation, Resources, Funding acquisition, Project administration. İK: Animal experiments, Methodology, Formal analysis, Data curation, Resources, Writing – original draft, Writing – review & editing, Funding acquisition, Project administration. MN: Methodology, Formal analysis, Writing – review & editing, Supervision.

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Correspondence to Mustafa Nazıroğlu.

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The study was approved by Kafkas University (KAU) Experimental Animal Research Center in Kars, Türkiye (Protocol number: KAU-HADYEK 2022/138), and all animals were handled in accordance with the standards of the National Experimental Animal Research Council of KAU.

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Kaya, M.M., Kaya, İ. & Nazıroğlu, M. Transient receptor potential channel stimulation induced oxidative stress and apoptosis in the colon of mice with colitis-associated colon cancer: modulator role of Sambucus ebulus L.. Mol Biol Rep 50, 2207–2220 (2023). https://doi.org/10.1007/s11033-022-08200-8

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