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Apoptosis-induced by TRAIL AND TNF-alpha in human multiple myeloma cells is not blocked by BCL-2
Y Gazitt1, P Shaughnessy, W Montgomery
1Department of Medicine/Hematology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, U S A.
Abstract:
TRAIL, the ligand for the newly discovered DR-4 and DR-5 receptor is a member of the tumour necrosis factor (TNF) family of death signal tranduction proteins with a mechanism of cell death, similar to the Fas and Fas ligand (Fas-L) system. Here, we provide first time evidence that TRAIL and TNF-alpha are potent inducers of apoptosis in multiple myeloma (MM) cell lines and freshly isolated myeloma cells. TRAIL effectively induced extensive apoptosis in 8226 and ARP-1 MM cells in a time- and dose-dependent manner reaching 80% within 48 h of treatment with a dose of 160 ng/ml. Bcl-2 transfected 8226 and ARP-1 cells were equally sensitive to apoptosis by TRAIL. Apoptosis with TNFalpha, reached >60% within 48 h of treatment with a dose of 160 ng/ml. In addition to MM cell lines, freshly isolated, flow-sorted myeloma cells from 8 different MM patients expressing variable levels of bcl-2 were equally sensitive to both TRAIL and TNF-alpha. We have previously shown that anti-Fas-induced apoptosis is not blocked by endogenous or ectopic bcl-2 in MM cell lines. Here we extend our observation with Fas to include TNF-alpha and TRAIL to the apoptotic signals that are not be blocked by bcl-2, in MM cells.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TNF-alpha effectively induce apoptosis in multiple myeloma cells. These signals are not blocked by Bcl-2, offering potential therapeutic strategies.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- TRAIL is a TNF-family protein that induces apoptosis via DR-4/DR-5 receptors.
- The Fas/Fas-L system also mediates apoptosis.
- Bcl-2 is an anti-apoptotic protein implicated in cancer resistance.
Purpose of the Study:
- To investigate the efficacy of TRAIL and TNF-alpha in inducing apoptosis in multiple myeloma (MM) cells.
- To determine if Bcl-2 expression affects MM cell sensitivity to TRAIL and TNF-alpha.
Main Methods:
- Treatment of MM cell lines (8226, ARP-1) and primary patient cells with TRAIL and TNF-alpha.
- Dose- and time-dependent apoptosis assays.
- Assessment of apoptosis in Bcl-2 transfected MM cells.
- Flow-sorted primary myeloma cells from MM patients were used.
Main Results:
- TRAIL induced apoptosis in MM cell lines in a time- and dose-dependent manner, reaching 80% at 160 ng/ml within 48h.
- TNF-alpha induced >60% apoptosis in MM cell lines within 48h at 160 ng/ml.
- Freshly isolated myeloma cells from 8 MM patients were sensitive to both TRAIL and TNF-alpha, irrespective of Bcl-2 levels.
- Bcl-2 did not block TRAIL- or TNF-alpha-induced apoptosis in MM cells.
Conclusions:
- TRAIL and TNF-alpha are potent inducers of apoptosis in multiple myeloma cell lines and primary cells.
- Bcl-2 does not inhibit apoptosis induced by TRAIL or TNF-alpha in multiple myeloma.
- These findings suggest TRAIL and TNF-alpha as promising therapeutic agents for multiple myeloma.