title: Apoptosis inhibitor TRIAP1 is a novel effector of drug resistance.
abstract: TP53-regulated inhibitor of apoptosis 1 (TRIAP1) is a novel apoptosis inhibitor that binds HSP70 in the cytoplasm and blocks the formation of the apoptosome and caspase-9 activation. TRIAP1 has been shown to be upregulated in many types of cancers; however, its role remains elusive. We determined the TRIAP1 mRNA levels in a panel of human tissues and found its expression to be ubiquitous. Normal breast, as well as non-tumorigenic breast cells, exhibited lower TRIAP1 mRNA levels than breast cancer cells or their drug-resistant derivatives. TRIAP1 is a small, evolutionarily conserved protein that is 76 amino acids long. We found that yeast cells, in which the TRIAP1 homologue was knocked out, had increased sensitivity to doxorubicin. Equally, RNA interference in breast cancer drug-resistant cells demonstrated that downregulation of TRIAP1 impaired cell growth in the presence of doxorubicin. As expected, caspase-9 activation was diminished after overexpression of TRIAP1 in drug-resistant cells. Importantly, stable transfections of a TRIAP1 expression plasmid in CAL51 cells led to a marked increase in the number of doxorubicin-resistant clones, that was abolished when cells expressed hairpins targeting TRIAP1. In addition, we showed that TRIAP1 expression was also triggered by estrogen deprivation in MCF-7 cells. Although both polyclonal and monoclonal antibodies generated for the present study failed to robustly detect TRIAP1, we demonstrated that TRIAP1 represents a novel marker for drug resistance in breast cancer cells and it may be used in the stratification of breast cancer patients once a suitable antibody has been developed. Equally, these studies open potential drug development strategies for blocking TRIAP1 activity and avoiding drug resistance.
authors.affiliation: Cancer Research Centre, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Adams
authors.affiliation: Cancer Research Centre, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Giulia
authors.initials: G
authors.lastname: Cazzanelli
authors.affiliation: Cancer Research Centre, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Sabeena
authors.initials: S
authors.lastname: Rasul
authors.affiliation: Cancer Research Centre, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Hitchinson
authors.affiliation: Cancer Research Centre, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Cancer Research Centre, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.affiliation: Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Selina
authors.initials: S
authors.lastname: Raguz
authors.affiliation: Cancer Research Centre, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Yagüe
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D053453:Caspase 9 / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D061986:MCF-7 Cells; D034741:RNA, Small Interfering / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D000903:Antibiotics, Antineoplastic; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C498536:TRIAP1 protein, human; D004317:Doxorubicin; C506433:CASP9 protein, human; D053453:Caspase 9