The Autophagy Inhibitor Bafilomycin Inhibits Antibody-Dependent Natural Killer Cell-Mediated Killing of Breast Carcinoma Cells

Bede, Ákos M.; Váróczy, Csongor; Polgár, Zsuzsanna; Fazekas, Gergő; Hegedűs, Csaba; Kókai, Endre; Kovács, Katalin; Virág, László

doi:10.3390/ijms26136273

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The Autophagy Inhibitor Bafilomycin Inhibits Antibody-Dependent Natural Killer Cell-Mediated Killing of Breast Carcinoma Cells

by

Ákos M. Bede

^1,2,†,

Csongor Váróczy

^1,2,†,

Zsuzsanna Polgár

^1,3

,

Gergő Fazekas

^1,4,

Csaba Hegedűs

^1,4

,

Endre Kókai

^1,3

,

Katalin Kovács

^1,4,* and

László Virág

^1,4,*

¹

Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem Tér 1, 4032 Debrecen, Hungary

²

National Academy of Scientist Education, Egyetem Tér 1, 4032 Debrecen, Hungary

³

Division of Dental Biochemistry, Department of Basic Medical Sciences, Faculty of Dentistry, University of Debrecen, Egyetem Tér 1, 4032 Debrecen, Hungary

⁴

HUN-REN-DE (Hungarian Reasearch Network—University of Debrecen) Cell Biology and Signaling Research Group, Egyetem Tér 1, 4032 Debrecen, Hungary

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2025, 26(13), 6273; https://doi.org/10.3390/ijms26136273 (registering DOI)

Submission received: 27 February 2025 / Revised: 24 June 2025 / Accepted: 25 June 2025 / Published: 28 June 2025

(This article belongs to the Special Issue Advances in Molecular Research on Cancer Treatments: Apoptosis, Autophagy, and Drug Selection)

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Abstract

The resistance of breast cancer cells to therapeutic antibodies such as anti-HER2 trastuzumab can be overcome by engaging natural killer (NK) cells for killing antibody-binding tumor cells via antibody-dependent cellular cytotoxicity (ADCC). Here, we investigated how autophagy modulation affects trastuzumab-mediated ADCC in HER2-positive JIMT1 breast cancer cells and NK cells. Autophagy inducers (rapamycin and resveratrol) had no significant impact, but the inhibitor bafilomycin nearly abolished ADCC. Protection occurred when either cancer or NK cells were pretreated, indicating dual effects. Bafilomycin reduced phosphatidylserine externalization, the loss of plasma membrane integrity, caspase-3/7 activity, and DNA fragmentation. It downregulated pro-apoptotic BAK1 and BAX without altering BCL-2. Additionally, bafilomycin decreased HER2 surface expression, impairing trastuzumab binding, and modulated immune regulators (STAT1, CD95, and PD-L1) in NK and/or in the cancer cells. Bafilomycin disrupted HER2 trafficking and induced HER2 internalization, leading to its accumulation in cytoplasmic vesicles. These findings show that autophagy inhibition by bafilomycin confers ADCC resistance by altering apoptosis, immune signaling, and HER2 dynamics. The study underscores autophagy’s role in antibody-based cancer therapy efficacy.

Keywords: natural killer cell; trastuzumab; antibody dependent cell-mediated cytotoxicity; apoptosis; autophagy

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MDPI and ACS Style

Bede, Á.M.; Váróczy, C.; Polgár, Z.; Fazekas, G.; Hegedűs, C.; Kókai, E.; Kovács, K.; Virág, L. The Autophagy Inhibitor Bafilomycin Inhibits Antibody-Dependent Natural Killer Cell-Mediated Killing of Breast Carcinoma Cells. Int. J. Mol. Sci. 2025, 26, 6273. https://doi.org/10.3390/ijms26136273

AMA Style

Bede ÁM, Váróczy C, Polgár Z, Fazekas G, Hegedűs C, Kókai E, Kovács K, Virág L. The Autophagy Inhibitor Bafilomycin Inhibits Antibody-Dependent Natural Killer Cell-Mediated Killing of Breast Carcinoma Cells. International Journal of Molecular Sciences. 2025; 26(13):6273. https://doi.org/10.3390/ijms26136273

Chicago/Turabian Style

Bede, Ákos M., Csongor Váróczy, Zsuzsanna Polgár, Gergő Fazekas, Csaba Hegedűs, Endre Kókai, Katalin Kovács, and László Virág. 2025. "The Autophagy Inhibitor Bafilomycin Inhibits Antibody-Dependent Natural Killer Cell-Mediated Killing of Breast Carcinoma Cells" International Journal of Molecular Sciences 26, no. 13: 6273. https://doi.org/10.3390/ijms26136273

APA Style

Bede, Á. M., Váróczy, C., Polgár, Z., Fazekas, G., Hegedűs, C., Kókai, E., Kovács, K., & Virág, L. (2025). The Autophagy Inhibitor Bafilomycin Inhibits Antibody-Dependent Natural Killer Cell-Mediated Killing of Breast Carcinoma Cells. International Journal of Molecular Sciences, 26(13), 6273. https://doi.org/10.3390/ijms26136273

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The Autophagy Inhibitor Bafilomycin Inhibits Antibody-Dependent Natural Killer Cell-Mediated Killing of Breast Carcinoma Cells

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