title: Inducible resistance of tumor cells to tumor necrosis factor-related apoptosis-inducing ligand receptor 2-mediated apoptosis by generation of a blockade at the death domain function.
abstract: Induction of tumor cell resistance to therapeutics has been a major obstacle in cancer therapy. Targeting of the death receptors by a natural ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), or agonistic monoclonal antibodies against TRAIL receptor 1 (TRAIL-R1) or TRAIL receptor 2 (TRAIL-R2) has been thought to be a promising cancer therapy. To determine whether tumor cells are able to generate a resistance to apoptosis induced by an anti-TRAIL-R2 antibody, TRA-8, we examined the apoptotic response of human breast and ovarian cancer cell lines after treatment with TRA-8. Our results show that tumor cell resistance to TRA-8 can be induced by repeated treatment of tumor cells with low, non-apoptosis-inducing doses of TRA-8. Interestingly, the induced resistance to apoptosis was not due to a global apoptotic defect in tumor cells but rather a selective defect in the TRAIL-R2 signaling pathway. Whereas TRA-8-treated tumor cells developed a selective resistance to TRAIL-R2-mediated apoptosis, the apoptotic responses induced by TRAIL, an anti-TRAIL-R1 antibody (2E12), and other apoptotic stimuli were not impaired. The expression levels of cell surface TRAIL-R2 were not altered and mutations of TRAIL-R2 were not found in the resistant cells. The induced TRA-8 resistance was due to a selective blockade at the level of the death domain and could be reversed by a wide array of chemotherapeutic agents. Proteomic analysis of death-inducing signaling complex formation during TRA-8 treatment shows that the translocation of TRAIL-R2-associated apoptotic proteins was significantly altered. Our results suggest that the prevention of tumor cell resistance to therapeutic agents that target the death receptors must be taken into consideration.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Sharmila
authors.initials: S
authors.lastname: Makhija
authors.forename: Donald
authors.initials: D
authors.lastname: Buchsbaum
authors.forename: Albert
authors.initials: A
authors.lastname: LoBuglio
authors.forename: Robert
authors.initials: R
authors.lastname: Kimberly
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha