Nigericin Induces Apoptosis in Primary Effusion Lymphoma Cells by Mitochondrial Membrane Hyperpolarization and β-Catenin Destabilization.

Abstract

BACKGROUND/AIM:

Primary effusion lymphoma (PEL) is classified as a rare non-Hodgkin's B-cell lymphoma that is caused by Kaposi's sarcoma-associated herpesvirus (KSHV); PEL cells are latently infected with KSHV. PEL is frequently resistant to conventional chemotherapies. Therefore, the development of novel therapeutic agents is urgently required. Nigericin, a H+ and K+ ionophore, possesses unique pharmacological effects. However, the effects of nigericin on PEL cells remain unknown.

MATERIALS AND METHODS:

We examined the cytotoxic effects of the K+ ionophores, nigericin, nonactin, and valinomycin, on various B-lymphoma cells including PEL. We also evaluated ionophore-induced changes in signaling pathways involved in KSHV-induced oncogenesis. Moreover, the effects of nigericin on mitochondrial membrane potential and viral reactivation in PEL were analyzed.

RESULTS:

Although the three tested ionophores inhibited the proliferation of several B-lymphoma cell lines, nigericin inhibited the proliferation of PEL cells compared to KSHV-negative cells. In PEL cells, nigericin disrupted the mitochondrial membrane potential and caused the release of cytochrome c, which triggered caspase-9-mediated apoptosis. Nigericin also induced both an increase in phosphorylated p38 MAPK and proteasomal degradation of β-catenin. Combination treatment of nigericin with the p38 MAPK inhibitor SB203580 potentiated the cytotoxic effects towards PEL cells, compared to either compound alone. Meanwhile, nigericin did not influence viral replication in PEL cells.

CONCLUSION:

Nigericin induces apoptosis in PEL cells by mitochondrial dysfunction and down-regulation of Wnt/β-catenin signaling. Thus, nigericin is a novel drug candidate for treating PEL without the risk of de novo KSHV infection.

• Authors: Haruka Umeyama, Zenpei Shigemi, Yusuke Baba, Naoko Hara, Tadashi Watanabe, Masahiro Fujimuro
• Journal: Anticancer research (Anticancer Res) Vol. 43 Issue 6 Pg. 2455-2465 (Jun 2023) ISSN: 1791-7530 [Electronic] Greece
• PMID: 37247906 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• Nigericin
• beta Catenin
• Antineoplastic Agents
• Ionophores
• p38 Mitogen-Activated Protein Kinases

Topics

• Humans
• Lymphoma, Primary Effusion (drug therapy, pathology)
• Nigericin (metabolism, pharmacology, therapeutic use)
• beta Catenin (metabolism)
• Mitochondrial Membranes (metabolism, pathology)
• Cell Line, Tumor
• Apoptosis
• Antineoplastic Agents (pharmacology)
• Herpesvirus 8, Human (physiology)
• Mitochondria
• Ionophores (metabolism, pharmacology, therapeutic use)
• p38 Mitogen-Activated Protein Kinases (metabolism)