Multiple mechanisms contribute to acquired TRAIL resistance in multiple myeloma
Fany V Ticona-Pérez1, Xi Chen1, Atanasio Pandiella2,3,4
1Instituto de Biología Molecular y Celular del Cáncer. CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
Abstract:
Multiple Myeloma (MM) prognosis has recently improved thanks to the incorporation of new therapies to the clinic. Nonetheless, it is still a non-curable malignancy. Targeting cancer cells with agents inducing cell death has been an appealing alternative investigated over the years, as is the case of TRAIL, an agonist of DR4 and DR5 death receptors. This pathway, involved in apoptosis triggering, has demonstrated efficacy on MM cells. In this research, we have investigated the sensitivity of a panel of MM cells to this agent and generated TRAIL-resistant models by continuous culture of sensitive cells with this peptide. Using genomic and biochemical approaches, the mechanisms underlying resistance were investigated. In TRAIL-resistant cells, a strong reduction in cell-surface receptor levels was detected and impaired the apoptotic machinery to respond to the treatment, enabling cells to efficiently form the Death Inducing Signalling Complex. In addition, an upregulation of the inhibitory protein c-FLIP was detected. Even though the manipulation of these proteins was able to modify cellular responses to TRAIL, it was not complete, pointing to other mechanisms involved in TRAIL resistance.
Insights
Researchers explored how Multiple Myeloma cells become resistant to TRAIL-induced cell death. Key findings include reduced death receptors and increased c-FLIP, impacting apoptosis signaling and treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Multiple Myeloma (MM) remains a non-curable malignancy despite recent therapeutic advancements.
- Targeting cancer cell death pathways, such as TRAIL-mediated apoptosis, is a promising therapeutic strategy for MM.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activates DR4 and DR5 death receptors, inducing apoptosis in cancer cells.
Purpose of the Study:
- To investigate the sensitivity of Multiple Myeloma cells to TRAIL treatment.
- To generate and characterize TRAIL-resistant Multiple Myeloma models.
- To elucidate the molecular mechanisms underlying TRAIL resistance in Multiple Myeloma.
Main Methods:
- Sensitivity testing of Multiple Myeloma cell lines to TRAIL.
- Generation of TRAIL-resistant cell models through continuous TRAIL exposure.
- Genomic and biochemical analyses to identify resistance mechanisms.
- Assessment of cell-surface receptor levels and apoptotic machinery function.
Main Results:
- TRAIL-resistant Multiple Myeloma cells exhibited significantly reduced cell-surface death receptor levels (DR4/DR5).
- Impaired apoptotic machinery prevented efficient Death Inducing Signalling Complex (DISC) formation in resistant cells.
- Upregulation of the inhibitory protein c-FLIP was observed in TRAIL-resistant cells.
- Partial restoration of TRAIL sensitivity was achieved by manipulating receptor levels and c-FLIP, but complete sensitivity was not recovered.
Conclusions:
- Multiple Myeloma cells can develop resistance to TRAIL-induced apoptosis through downregulation of death receptors and upregulation of c-FLIP.
- These alterations impair the apoptotic signaling pathway, hindering DISC formation and cell death.
- Additional, yet unidentified, mechanisms likely contribute to TRAIL resistance in Multiple Myeloma, warranting further investigation.
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