Blockade of Exosome Release Alters Her2 Trafficking to the Plasma Membrane and Gives a Boost to Trastuzumab

Blockade of Exosome Release Alters Her2 Trafficking to the Plasma Membrane and Gives a Boost to Trastuzumab Publisher Pubmed

Hosseini R¹ ; Asefkabiri L² ; Sarvnaz H³ ; Ghanavatinejad A³ ; Rezayat F¹ ; Eskandari N¹ ; Akbari ME²

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1. Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2. Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3. Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

Source: Clinical and Translational Oncology Published:2023

Abstract

Objective(s): Exosomal HER2 has been evidenced to interfere with antibody-induced anti-tumor effects. However, whether the blockade of HER2+ exosomes release would affect antibody-mediated tumor inhibition has yet to be investigated. Methods: Exosomes derived from BT-474, SK-BR3 and SK-OV3 (HER2-overexpressing tumor cells) and MDA-MB-231 cells (HER2 negative) were purified and characterized by bicinchoninic acid (BCA) assay, western blotting and Transmission electron microscopy (TEM). Inhibition of exosome release was achieved by neutral sphingomyelinase-2 (nSMase-2) inhibitor, GW4869. The effects of exosome blockade on the anti-proliferative effects, apoptosis induction, and antibody-mediated cellular cytotoxicity (ADCC) activity of Trastuzumab were examined using MTT, flow cytometry, and LDH release assays. Also, the effects of exosome inhibition on the surface expression and endocytosis/internalization of HER2 were studied by flow cytometry. Results: Purified exosomes derived from HER2 overexpressing cancer cells were positive for HER2 protein. Blockade of exosome release was able to significantly improve apoptosis induction, anti-proliferative and ADCC responses of Trastuzumab dose dependently. The pretreatment of Trastuzumab/purified NK cells, but not PBMCs, with HER2+ exosomes could also decrease the ADCC effects of Trastuzumab. Exosome inhibition also remarkably downregulated surface HER2 levels in a time-dependent manner, but does not affect its endocytosis/internalization. Conclusion: Based on our findings, HER2+ exosomes may benefit tumor progression by dually suppressing Trastuzumab-induced tumor growth inhibition and cytotoxicity of NK cells. It seems that concomitant blocking of exosome release might be an effective approach for improving the therapeutic effects of Trastuzumab, and potentially other HER2-directed mAbs. In addition, the exosome secretion pathway possibly contributes to the HER2 trafficking to plasma membrane, since the blockade of exosome secretion decreased surface HER2 levels. © 2022, The Author(s), under exclusive licence to Federacion de Sociedades Espanolas de Oncologia (FESEO).

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Style	Citing Format
MLA	Hosseini R, et al.. "Blockade of Exosome Release Alters Her2 Trafficking to the Plasma Membrane and Gives a Boost to Trastuzumab." Clinical and Translational Oncology, vol. 25, no. 1, 2023, pp. 185-198.
APA	Hosseini R, Asefkabiri L, Sarvnaz H, Ghanavatinejad A, Rezayat F, Eskandari N, Akbari ME (2023). Blockade of Exosome Release Alters Her2 Trafficking to the Plasma Membrane and Gives a Boost to Trastuzumab. Clinical and Translational Oncology, 25(1), 185-198.
Chicago	Hosseini R, Asefkabiri L, Sarvnaz H, Ghanavatinejad A, Rezayat F, Eskandari N, Akbari ME. "Blockade of Exosome Release Alters Her2 Trafficking to the Plasma Membrane and Gives a Boost to Trastuzumab." Clinical and Translational Oncology 25, no. 1 (2023): 185-198.
Harvard	Hosseini R et al. (2023) 'Blockade of Exosome Release Alters Her2 Trafficking to the Plasma Membrane and Gives a Boost to Trastuzumab', Clinical and Translational Oncology, 25(1), pp. 185-198.
Vancouver	Hosseini R, Asefkabiri L, Sarvnaz H, Ghanavatinejad A, Rezayat F, Eskandari N, et al.. Blockade of Exosome Release Alters Her2 Trafficking to the Plasma Membrane and Gives a Boost to Trastuzumab. Clinical and Translational Oncology. 2023;25(1):185-198.
BibTex	@article{ author = {Hosseini R and Asefkabiri L and Sarvnaz H and Ghanavatinejad A and Rezayat F and Eskandari N and Akbari ME}, title = {Blockade of Exosome Release Alters Her2 Trafficking to the Plasma Membrane and Gives a Boost to Trastuzumab}, journal = {Clinical and Translational Oncology}, volume = {25}, number = {1}, pages = {185-198}, year = {2023} }
RIS	TY - JOUR AU - Hosseini R AU - Asefkabiri L AU - Sarvnaz H AU - Ghanavatinejad A AU - Rezayat F AU - Eskandari N AU - Akbari ME TI - Blockade of Exosome Release Alters Her2 Trafficking to the Plasma Membrane and Gives a Boost to Trastuzumab JO - Clinical and Translational Oncology VL - 25 IS - 1 SP - 185 EP - 198 PY - 2023 ER -

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