title: Borrelidin Induces the Unfolded Protein Response in Oral Cancer Cells and Chop-Dependent Apoptosis.
abstract: Oral squamous cell carcinoma (OSCC) is the most common cancer affecting the oral cavity, and US clinics will register about 30,000 new patients in 2015. Current treatment modalities include chemotherapy, surgery, and radiotherapy, which often result in astonishing disfigurement. Cancers of the head and neck display enhanced levels of glucose-regulated proteins and translation initiation factors associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Previous work demonstrated that chemically enforced UPR could overwhelm these adaptive features and selectively kill malignant cells. The threonyl-tRNA synthetase (ThRS) inhibitor borrelidin and two congeners were discovered in a cell-based chemical genomic screen. Borrelidin increased XBP1 splicing and led to accumulation of phosphorylated eIF2α and UPR-associated genes, prior to death in panel of OSCC cells. Murine embryonic fibroblasts (MEFs) null for GCN2 and PERK were less able to accumulate UPR markers and were resistant to borrelidin. This study demonstrates that UPR induction is a feature of ThRS inhibition and adds to a growing body of literature suggesting ThRS inhibitors might selectively target cancer cells.
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors.forename: Alpa
authors.initials: A
authors.lastname: Sidhu
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Miller
authors.affiliation: Life Sciences Institute and Departments of Medicinal Chemistry, Chemistry, Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Ashootosh
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Garshott
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Brownell
authors.affiliation: Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry , Ann Arbor, Michigan 48109, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Chiego
authors.affiliation: Life Sciences Institute and Departments of Medicinal Chemistry, Chemistry, Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Carl
authors.initials: C
authors.lastname: Arevang
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Jackson
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors.forename: Shelby A
authors.initials: SA
authors.lastname: Bechler
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors.forename: Michael U
authors.initials: MU
authors.lastname: Callaghan
authors.affiliation: Department of Otolaryngology, Wayne State University and Karmanos Cancer Institute , Detroit, Michigan 48201, United States.
authors.forename: George H
authors.initials: GH
authors.lastname: Yoo
authors.affiliation: Department of Pathology, Wayne State University and Karmanos Cancer Institute , Detroit, Michigan 48201, United States.
authors.forename: Seema
authors.initials: S
authors.lastname: Sethi
authors.affiliation: Department of Otolaryngology, Wayne State University and Karmanos Cancer Institute , Detroit, Michigan 48201, United States.
authors.forename: Ho-Sheng
authors.initials: HS
authors.lastname: Lin
authors.affiliation: School of Business Administration, Oakland University , Rochester, Michigan 48309, United States.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Callaghan
authors.affiliation: Instituto Nacional de Biodiversidad, CIPRONA-Escuela de Química, Universidad de Costa Rica , 3100 Heredia, Costa Rica.
authors.forename: Giselle
authors.initials: G
authors.lastname: Tamayo-Castillo
authors.affiliation: Life Sciences Institute and Departments of Medicinal Chemistry, Chemistry, Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: David H
authors.initials: DH
authors.lastname: Sherman
authors.affiliation: Degenerative Disease Research Program, Center for Cancer Research, Sanford|Burnham Medical Research Institute , La Jolla, California 92037, United States.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Wayne State University School of Medicine , Detroit, Michigan 48201, United States ; Department of Otolaryngology, Wayne State University and Karmanos Cancer Institute , Detroit, Michigan 48201, United States ; Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute , Detroit, Michigan 48201, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fribley
keywords: Chop; ER stress; UPR; Xbp1, BiP/GRP78; borrelidin; high throughput screen; natural products; oral cancer; oral squamous cell carcinoma; protein folding