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Unique resistance of breast carcinoma cell line T47D to TRAIL but not anti-Fas is linked to p43cFLIPL

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Abstract

The majority of breast cancer cell lines are resistant to tumor necrosis factor -related apoptosis inducing ligand (TRAIL) induced apoptosis. TRAIL and Fas receptor death-inducing signaling complex (DISCs) formation are similar and involve ligand-dependent recruitment of FADD and caspase-8. We have found that the breast carcinoma cell line T47D is an unusual example of selective sensitivity to anti-Fas mAb treatment but resistant to TRAIL. Therefore, a detailed comparison of these two signaling pathways in one cell line should provide insight into the mechanism of TRAIL resistance. We observed that only anti-Fas mAb induces caspase activation and cell death in T47D. Further, FADD and caspase-8 interact with both TRAIL-R1 and TRAIL-R2, and that the amount of caspase-8 recruited by Fas-, TRAIL-R1 and TRAIL-R2 are the same. cFLIPS and cFLIPR isoforms block death receptor-induced apoptosis by inhibiting caspase-8 activation at the DISC; the role of cFLIPL at the DISC is still controversial. It has been suggested that the presence of the cleaved form of FLIPL-p43 at the DISC prevents caspase-8 cleavage. We found that both TRAIL and anti-Fas mAb-induced DISCs contain the cleaved form of p43 cFLIPL and its amount at the Fas DISC was higher compared to the TRAIL DISC. We also found that inhibition of cFLIPL expression in T47D cells decreased Fas-mediated caspase-8 activation and activation of effector caspases. We propose that in T47D p43 cFLIPL in the Fas-DISC may promote caspase-8 activation. The mechanism by which different amounts of p43cFLIPL regulates caspase-8 activation remains to be investigated.

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Authors and Affiliations

  1. Department of Pathology, The University of Iowa, 200 Hawkins Drive, C670, Iowa City, IA, 52242-1087, USA

    Natalya V. Guseva, Oskar W. Rokhlin, Agshin F. Taghiyev & Michael B. Cohen

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  1. Natalya V. Guseva
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  2. Oskar W. Rokhlin
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  3. Agshin F. Taghiyev
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  4. Michael B. Cohen
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Correspondence to Michael B. Cohen.

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Guseva, N.V., Rokhlin, O.W., Taghiyev, A.F. et al. Unique resistance of breast carcinoma cell line T47D to TRAIL but not anti-Fas is linked to p43cFLIPL . Breast Cancer Res Treat 107, 349–357 (2008). https://doi.org/10.1007/s10549-007-9563-2

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  • DOI: https://doi.org/10.1007/s10549-007-9563-2

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