Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to Bortezomib
Several studies have shown that diverse components of the bone marrow (BM) microenvironment play a central role in the progression, pathophysiology, and drug resistance in multiple myeloma (MM). In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown...
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/8157 |
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| author | P. M. Rojas-Zambrano J. E. Meyer-Herrera P. F. Ruiz-Aparicio J. P. Vernot |
| author_facet | P. M. Rojas-Zambrano J. E. Meyer-Herrera P. F. Ruiz-Aparicio J. P. Vernot |
| author_sort | P. M. Rojas-Zambrano |
| collection | DOAJ |
| description | Several studies have shown that diverse components of the bone marrow (BM) microenvironment play a central role in the progression, pathophysiology, and drug resistance in multiple myeloma (MM). In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-κB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-κB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma. Considering that H929 cells were also directly susceptible to PKC and NF-κB inhibition, we showed that treatment of co-cultures with the HKPS peptide and BAY11-7082, followed by bortezomib, increased H929 cell death. Therefore, targeting simultaneously connected signalling elements of BM-MSC responsible for MM cells support with compounds that also have anti-MM activity can be an improved treatment strategy. |
| first_indexed | 2024-03-11T04:16:06Z |
| format | Article |
| id | doaj.art-5b0fee16b2604dea9d942d8a86998d64 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:16:06Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5b0fee16b2604dea9d942d8a86998d642023-11-17T23:05:43ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-01249815710.3390/ijms24098157Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to BortezomibP. M. Rojas-Zambrano0J. E. Meyer-Herrera1P. F. Ruiz-Aparicio2J. P. Vernot3Grupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, ColombiaGrupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, ColombiaGrupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, ColombiaGrupo de Investigación Fisiología Celular y Molecular, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá 111321, ColombiaSeveral studies have shown that diverse components of the bone marrow (BM) microenvironment play a central role in the progression, pathophysiology, and drug resistance in multiple myeloma (MM). In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-κB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-κB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma. Considering that H929 cells were also directly susceptible to PKC and NF-κB inhibition, we showed that treatment of co-cultures with the HKPS peptide and BAY11-7082, followed by bortezomib, increased H929 cell death. Therefore, targeting simultaneously connected signalling elements of BM-MSC responsible for MM cells support with compounds that also have anti-MM activity can be an improved treatment strategy.https://www.mdpi.com/1422-0067/24/9/8157mesenchymal stem/stromal cellsmicroenvironmentmultiple myelomaPKCNF-κBbortezomib |
| spellingShingle | P. M. Rojas-Zambrano J. E. Meyer-Herrera P. F. Ruiz-Aparicio J. P. Vernot Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to Bortezomib International Journal of Molecular Sciences mesenchymal stem/stromal cells microenvironment multiple myeloma PKC NF-κB bortezomib |
| title | Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to Bortezomib |
| title_full | Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to Bortezomib |
| title_fullStr | Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to Bortezomib |
| title_full_unstemmed | Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to Bortezomib |
| title_short | Simultaneously Targeting Two Coupled Signalling Molecules in the Mesenchymal Stem Cell Support Efficiently Sensitises the Multiple Myeloma Cell Line H929 to Bortezomib |
| title_sort | simultaneously targeting two coupled signalling molecules in the mesenchymal stem cell support efficiently sensitises the multiple myeloma cell line h929 to bortezomib |
| topic | mesenchymal stem/stromal cells microenvironment multiple myeloma PKC NF-κB bortezomib |
| url | https://www.mdpi.com/1422-0067/24/9/8157 |
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