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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/4/767 |
| _version_ | 1797437122830925824 |
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| author | Grazia Scandura Cesarina Giallongo Fabrizio Puglisi Alessandra Romano Nunziatina Laura Parrinello Tatiana Zuppelli Lucia Longhitano Sebastiano Giallongo Michelino Di Rosa Giuseppe Musumeci Roberto Motterlini Roberta Foresti Giuseppe Alberto Palumbo Giovanni Li Volti Francesco Di Raimondo Daniele Tibullo |
| author_facet | Grazia Scandura Cesarina Giallongo Fabrizio Puglisi Alessandra Romano Nunziatina Laura Parrinello Tatiana Zuppelli Lucia Longhitano Sebastiano Giallongo Michelino Di Rosa Giuseppe Musumeci Roberto Motterlini Roberta Foresti Giuseppe Alberto Palumbo Giovanni Li Volti Francesco Di Raimondo Daniele Tibullo |
| author_sort | Grazia Scandura |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T11:14:20Z |
| format | Article |
| id | doaj.art-c8d39cb351654d97b0b17d10102c0ef2 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T11:14:20Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-c8d39cb351654d97b0b17d10102c0ef22023-12-01T00:36:34ZengMDPI AGAntioxidants2076-39212022-04-0111476710.3390/antiox11040767TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib TreatmentGrazia Scandura0Cesarina Giallongo1Fabrizio Puglisi2Alessandra Romano3Nunziatina Laura Parrinello4Tatiana Zuppelli5Lucia Longhitano6Sebastiano Giallongo7Michelino Di Rosa8Giuseppe Musumeci9Roberto Motterlini10Roberta Foresti11Giuseppe Alberto Palumbo12Giovanni Li Volti13Francesco Di Raimondo14Daniele Tibullo15Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, ItalyDepartment of Scienze Mediche Chirurgiche e Tecnologie Avanzate “G.F. Ingrassia”, University of Catania, 95123 Catania, ItalyDivision of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, ItalyDivision of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, ItalyDivision of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalyFaculty of Health, University Paris-Est Créteil, INSERM, IMRB, 94010 Créteil, FranceFaculty of Health, University Paris-Est Créteil, INSERM, IMRB, 94010 Créteil, FranceDepartment of Scienze Mediche Chirurgiche e Tecnologie Avanzate “G.F. Ingrassia”, University of Catania, 95123 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalyDivision of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, ItalyDepartment of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalyRelapse 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.https://www.mdpi.com/2076-3921/11/4/767multiple myelomaTLR4/HO-1 crosstalkmitochondriabortezomib |
| spellingShingle | Grazia Scandura Cesarina Giallongo Fabrizio Puglisi Alessandra Romano Nunziatina Laura Parrinello Tatiana Zuppelli Lucia Longhitano Sebastiano Giallongo Michelino Di Rosa Giuseppe Musumeci Roberto Motterlini Roberta Foresti Giuseppe Alberto Palumbo Giovanni Li Volti Francesco Di Raimondo Daniele Tibullo TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib Treatment Antioxidants multiple myeloma TLR4/HO-1 crosstalk mitochondria bortezomib |
| 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 | multiple myeloma TLR4/HO-1 crosstalk mitochondria bortezomib |
| url | https://www.mdpi.com/2076-3921/11/4/767 |
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