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Unique resistance of breast carcinoma cell line T47D to TRAIL but not anti-Fas is linked to p43cFLIP(L).
Breast Cancer Res Treat. 2008 Feb; 107(3):349-57.BC

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. cFLIP(S) and cFLIP(R)isoforms block death receptor-induced apoptosis by inhibiting caspase-8 activation at the DISC; the role of cFLIP(L)at the DISC is still controversial. It has been suggested that the presence of the cleaved form of FLIP(L)-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 cFLIP(L) and its amount at the Fas DISC was higher compared to the TRAIL DISC. We also found that inhibition of cFLIP(L) expression in T47D cells decreased Fas-mediated caspase-8 activation and activation of effector caspases. We propose that in T47D p43 cFLIP(L) in the Fas-DISC may promote caspase-8 activation. The mechanism by which different amounts of p43cFLIP(L) regulates caspase-8 activation remains to be investigated.

Authors+Show Affiliations

Department of Pathology, The University of Iowa, 200 Hawkins Drive, C670, Iowa City, IA 52242-1087, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17453339

Citation

Guseva, Natalya V., et al. "Unique Resistance of Breast Carcinoma Cell Line T47D to TRAIL but Not anti-Fas Is Linked to P43cFLIP(L)." Breast Cancer Research and Treatment, vol. 107, no. 3, 2008, pp. 349-57.
Guseva NV, Rokhlin OW, Taghiyev AF, et al. Unique resistance of breast carcinoma cell line T47D to TRAIL but not anti-Fas is linked to p43cFLIP(L). Breast Cancer Res Treat. 2008;107(3):349-57.
Guseva, N. V., Rokhlin, O. W., Taghiyev, A. F., & Cohen, M. B. (2008). Unique resistance of breast carcinoma cell line T47D to TRAIL but not anti-Fas is linked to p43cFLIP(L). Breast Cancer Research and Treatment, 107(3), 349-57.
Guseva NV, et al. Unique Resistance of Breast Carcinoma Cell Line T47D to TRAIL but Not anti-Fas Is Linked to P43cFLIP(L). Breast Cancer Res Treat. 2008;107(3):349-57. PubMed PMID: 17453339.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Unique resistance of breast carcinoma cell line T47D to TRAIL but not anti-Fas is linked to p43cFLIP(L). AU - Guseva,Natalya V, AU - Rokhlin,Oskar W, AU - Taghiyev,Agshin F, AU - Cohen,Michael B, Y1 - 2007/04/24/ PY - 2006/09/01/received PY - 2007/03/09/accepted PY - 2007/4/25/pubmed PY - 2008/5/7/medline PY - 2007/4/25/entrez SP - 349 EP - 57 JF - Breast cancer research and treatment JO - Breast Cancer Res Treat VL - 107 IS - 3 N2 - 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. cFLIP(S) and cFLIP(R)isoforms block death receptor-induced apoptosis by inhibiting caspase-8 activation at the DISC; the role of cFLIP(L)at the DISC is still controversial. It has been suggested that the presence of the cleaved form of FLIP(L)-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 cFLIP(L) and its amount at the Fas DISC was higher compared to the TRAIL DISC. We also found that inhibition of cFLIP(L) expression in T47D cells decreased Fas-mediated caspase-8 activation and activation of effector caspases. We propose that in T47D p43 cFLIP(L) in the Fas-DISC may promote caspase-8 activation. The mechanism by which different amounts of p43cFLIP(L) regulates caspase-8 activation remains to be investigated. SN - 0167-6806 UR - https://www.unboundmedicine.com/medline/citation/17453339/Unique_resistance_of_breast_carcinoma_cell_line_T47D_to_TRAIL_but_not_anti_Fas_is_linked_to_p43cFLIP_L__ L2 - https://doi.org/10.1007/s10549-007-9563-2 DB - PRIME DP - Unbound Medicine ER -