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Pharmacological inhibition of p38 potentiates antimicrobial peptide TP4-induced cell death in glioblastoma cells

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Abstract

Glioblastoma is the most common and deadly type of brain cancer. The poor prognosis may be largely attributed to inadequate disease response to current chemotherapeutic agents. Activation of p38 is associated with deleterious outcomes in glioblastoma patients, as its signaling mediates chemoresistance mechanisms. Antimicrobial peptide tilapia piscidin (TP) 4 was identified from Nile tilapia (Oreochromis niloticus) and exhibits strong bactericidal effects on Gram-positive and Gram-negative bacteria. TP4 also has anticancer activity toward human triple-negative breast cancer cells and glioblastoma cells. In the present study, we tested the cytotoxic effects of combined TP4 and p38 inhibitors on glioblastoma U251 cells. We found that the combination of TP4 and p38 inhibitors (SB202190 and VX-745) enhanced cytotoxicity in U251 glioblastoma cells but not noncancerous neural cells. Cytotoxicity from the combination treatments proceeded via necrosis and not apoptosis. Mechanistically, SB202190 potentiated TP4-induced mitochondrial dysfunction, reactive oxygen species generation and unbalanced antioxidant status, which resulted in necrotic cell death. Thus, we demonstrated for the first time that combinations of TP4 and p38 inhibitors have the potential to preferentially target glioblastoma cells, while sparing noncancerous neural cells.

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Abbreviations

TP4:

Tilapia piscidin 4

TMZ:

Temozolomide

BCNU:

Bis-chloroethylnitrosourea

Nrf2:

Nuclear factor erythroid 2-related factor 2

VEGF:

Vascular endothelial growth factor

DHE:

Dihydroethidium

PI:

Propidium iodide

TMRE:

Tetramethylrhodamine, ethyl ester

DCF-DA:

2′,7′-Dichlorodihydrofluorescein diacetate

NAC:

N-Acetyl-l-cysteine

UCP:

Uncoupling protein

SOD:

Superoxide dismutase

DMEM:

Dulbecco’s modified Eagle’s medium

RIP3:

Receptor-interacting protein kinase 3

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Acknowledgements

This research was supported by intramural funding from the Marine Research Station (Jiaushi, Ilan), Institute of Cellular and Organismic Biology, Academia Sinica to Dr. Jyh-Yih Chen. We thank Dr. Pei-Jung Lu, National Cheng Kung University (Taiwan), for kindly providing the U251 human glioblastoma cell line.

Funding

This research was supported by intramural funding from the Marine Research Station (Jiaushi, Ilan), Institute of Cellular and Organismic Biology, Academia Sinica to Jyh-Yih Chen (Research Fellow).

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Bor-Chyuan Su

  2. Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, 23-10 Dahuen Road, Jiaushi, Ilan, 262, Taiwan

    Jyh-Yih Chen

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B-CS performed the experiments; B-CS analyzed the data; B-CS contributed reagents/materials/analysis tools; B-CS and J-YC wrote the paper.

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Correspondence to Jyh-Yih Chen.

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Su, BC., Chen, JY. Pharmacological inhibition of p38 potentiates antimicrobial peptide TP4-induced cell death in glioblastoma cells. Mol Cell Biochem 464, 1–9 (2020). https://doi.org/10.1007/s11010-019-03643-3

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