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TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib Treatment
Relapse in multiple myeloma (MM) decreases therapy efficiency through unclear mechanisms of chemoresistance. Since our group previously demonstrated that heme oxygenase-1 (HO-1) and Toll-like receptor 4 (TLR4) are two signaling pathways protecting MM cells from the proteasome inhibitor bortezomib (B...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031632/ https://www.ncbi.nlm.nih.gov/pubmed/35453452 http://dx.doi.org/10.3390/antiox11040767 |
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author | Scandura, Grazia Giallongo, Cesarina Puglisi, Fabrizio Romano, Alessandra Parrinello, Nunziatina Laura Zuppelli, Tatiana Longhitano, Lucia Giallongo, Sebastiano Di Rosa, Michelino Musumeci, Giuseppe Motterlini, Roberto Foresti, Roberta Palumbo, Giuseppe Alberto Li Volti, Giovanni Di Raimondo, Francesco Tibullo, Daniele |
author_facet | Scandura, Grazia Giallongo, Cesarina Puglisi, Fabrizio Romano, Alessandra Parrinello, Nunziatina Laura Zuppelli, Tatiana Longhitano, Lucia Giallongo, Sebastiano Di Rosa, Michelino Musumeci, Giuseppe Motterlini, Roberto Foresti, Roberta Palumbo, Giuseppe Alberto Li Volti, Giovanni Di Raimondo, Francesco Tibullo, Daniele |
author_sort | Scandura, Grazia |
collection | PubMed |
description | Relapse in multiple myeloma (MM) decreases therapy efficiency through unclear mechanisms of chemoresistance. Since our group previously demonstrated that heme oxygenase-1 (HO-1) and Toll-like receptor 4 (TLR4) are two signaling pathways protecting MM cells from the proteasome inhibitor bortezomib (BTZ), we here evaluated their cross-regulation by a pharmacological approach. We found that cell toxicity and mitochondrial depolarization by BTZ were increased upon inhibition of HO-1 and TLR4 by using tin protoporphyrin IX (SnPP) and TAK-242, respectively. Furthermore, the combination of TAK-242 and BTZ activated mitophagy and decreased the unfolded protein response (UPR) survival pathway in association with a downregulation in HO-1 expression. Notably, BTZ in combination with SnPP induced effects mirroring the treatment with TAK-242/BTZ, resulting in a blockade of TLR4 upregulation. Interestingly, treatment of cells with either hemin, an HO-1 inducer, or supplementation with carbon monoxide (CO), a by-product of HO-1 enzymatic activity, increased TLR4 expression. In conclusion, we showed that treatment of MM cells with BTZ triggers the TLR4/HO-1/CO axis, serving as a stress-responsive signal that leads to increased cell survival while protecting mitochondria against BTZ and ultimately promoting drug resistance. |
format | Online Article Text |
id | pubmed-9031632 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-90316322022-04-23 TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib Treatment Scandura, Grazia Giallongo, Cesarina Puglisi, Fabrizio Romano, Alessandra Parrinello, Nunziatina Laura Zuppelli, Tatiana Longhitano, Lucia Giallongo, Sebastiano Di Rosa, Michelino Musumeci, Giuseppe Motterlini, Roberto Foresti, Roberta Palumbo, Giuseppe Alberto Li Volti, Giovanni Di Raimondo, Francesco Tibullo, Daniele Antioxidants (Basel) Article Relapse in multiple myeloma (MM) decreases therapy efficiency through unclear mechanisms of chemoresistance. Since our group previously demonstrated that heme oxygenase-1 (HO-1) and Toll-like receptor 4 (TLR4) are two signaling pathways protecting MM cells from the proteasome inhibitor bortezomib (BTZ), we here evaluated their cross-regulation by a pharmacological approach. We found that cell toxicity and mitochondrial depolarization by BTZ were increased upon inhibition of HO-1 and TLR4 by using tin protoporphyrin IX (SnPP) and TAK-242, respectively. Furthermore, the combination of TAK-242 and BTZ activated mitophagy and decreased the unfolded protein response (UPR) survival pathway in association with a downregulation in HO-1 expression. Notably, BTZ in combination with SnPP induced effects mirroring the treatment with TAK-242/BTZ, resulting in a blockade of TLR4 upregulation. Interestingly, treatment of cells with either hemin, an HO-1 inducer, or supplementation with carbon monoxide (CO), a by-product of HO-1 enzymatic activity, increased TLR4 expression. In conclusion, we showed that treatment of MM cells with BTZ triggers the TLR4/HO-1/CO axis, serving as a stress-responsive signal that leads to increased cell survival while protecting mitochondria against BTZ and ultimately promoting drug resistance. MDPI 2022-04-12 /pmc/articles/PMC9031632/ /pubmed/35453452 http://dx.doi.org/10.3390/antiox11040767 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Scandura, Grazia Giallongo, Cesarina Puglisi, Fabrizio Romano, Alessandra Parrinello, Nunziatina Laura Zuppelli, Tatiana Longhitano, Lucia Giallongo, Sebastiano Di Rosa, Michelino Musumeci, Giuseppe Motterlini, Roberto Foresti, Roberta Palumbo, Giuseppe Alberto Li Volti, Giovanni Di Raimondo, Francesco Tibullo, Daniele TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib Treatment |
title | TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib Treatment |
title_full | TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib Treatment |
title_fullStr | TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib Treatment |
title_full_unstemmed | TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib Treatment |
title_short | TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib Treatment |
title_sort | tlr4 signaling and heme oxygenase-1/carbon monoxide pathway crosstalk induces resiliency of myeloma plasma cells to bortezomib treatment |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031632/ https://www.ncbi.nlm.nih.gov/pubmed/35453452 http://dx.doi.org/10.3390/antiox11040767 |
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