Blocking of Transient Receptor Potential Vanilloid 1 (TRPV1) promotes terminal mitophagy in multiple myeloma, disturbing
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RESEARCH
Blocking of Transient Receptor Potential Vanilloid 1 (TRPV1) promotes terminal mitophagy in multiple myeloma, disturbing calcium homeostasis and targeting ubiquitin pathway and bortezomib‑induced unfolded protein response Katia Beider1, Evgenia Rosenberg1, Valeria Dimenshtein‑Voevoda1, Yaarit Sirovsky1, Julia Vladimirsky1, Hila Magen1, Olga Ostrovsky1, Avichai Shimoni1, Zohar Bromberg2, Lola Weiss2, Amnon Peled2 and Arnon Nagler1*
Abstract Background: Chemoresistance remains a major treatment obstacle in multiple myeloma (MM). Novel new therapies are thus in need. Transient Receptor Potential Vanilloid type 1 (TRPV1) is a calcium-permeable ion channel that has been demonstrated to be expressed in solid tumors. Calcium channels have been shown to be involved in the regula‑ tion of cell proliferation, chemoresistance, migration and invasion. The aim of the current study was to evaluate its possible role in MM. Methods: Pharmacological inhibitor was used to evaluate the role of TRPV1 in MM cell lines and primary MM cells. Flow cytometry, molecular analysis, fluorescent microscopy, proteomic analysis and xenograft in vivo model of MM with BM involvement were employed to assess the effect of TRPV1 inhibition and decipher its unique mechanism of action in MM. Results: TRPV1 was found to be expressed by MM cell lines and primary MM cells. TRPV1 inhibition using the antago‑ nist AMG9810-induced MM cell apoptosis and synergized with bortezomib, overcoming both CXCR4-dependent stroma-mediated and acquired resistance. In accordance, AMG9810 suppressed the expression and activation of CXCR4 in MM cells. TRPV1 inhibition increased mitochondrial calcium levels with subsequent mitochondrial ROS accu‑ mulation and depolarization. These effects were reversed by calcium chelation, suggesting the role of calcium pertur‑ bations in oxidative stress and mitochondrial destabilization. Furthermore, AMG9810 abolished bortezomib-induced accumulation of mitochondrial HSP70 and suppressed protective mitochondrial unfolded protein response. Proteom‑ ics revealed unique molecular signature related to the modification of ubiquitin signaling pathway. Consequently, 38 proteins related to the ubiquitylation machinery were downregulated upon combined bortezomib/AMG9810
*Correspondence: [email protected] 1 Division of Hematology, CBB and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Aviv University, Tel‑Hashomer, Ramat Gan, Israel Full list of author information is available at the end of the article © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless ind
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