title: Cantharidins induce ER stress and a terminal unfolded protein response in OSCC.
abstract: Mortality and morbidity associated with oral squamous cell carcinoma (OSCC) remain unacceptably high with disfiguring treatment options and a death rate of 1 per hour in the United States. The approval of cituximab for advanced OSCC has been the only new treatment for these patients since the 1970s, although it has not significantly increased overall survival. To address the paucity of effective new therapies, we undertook a high-throughput screen to discover small molecules and natural products that could induce endoplasmic reticulum (ER) stress and enforce a terminal unfolded protein response (UPR) in OSCC. The terpenoid cantharidin (CNT), previously used to treat various malignancies in culture-specific medical practices for over 2,000 y, emerged as a hit. CNT and its analog, cantharidic acid, potently induced protein and gene expression profiles consistent with the activation of ER stress, the UPR, and apoptosis in OSCC cells. Murine embryonic fibroblasts null for the UPR-associated transcription factors Atf4 or Chop were significantly protected from CNT, implicating a key role for the UPR in the death response. These data validate that our high-throughput screen can identify novel modulators of UPR signaling and that such compounds might provide a new therapeutic approach to treating patients with OSCC.
authors.affiliation: The Key Laboratory of Pathiobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China Carmen and Ann Adams Department of Pediatrics, Division of Hematology Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Division of Hematology Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Garshott
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Division of Hematology Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Brownell
authors.affiliation: Department of Otolaryngology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: G H
authors.initials: GH
authors.lastname: Yoo
authors.affiliation: Department of Otolaryngology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: H-S
authors.initials: HS
authors.lastname: Lin
authors.affiliation: Department of Otolaryngology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Freeburg
authors.affiliation: Department of Otolaryngology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: N G
authors.initials: NG
authors.lastname: Yoo
authors.affiliation: Degenerative Diseases Program, Sanford|Burnham Medical Research Institute, La Jolla, CA and Department of Pharmacology, University of California Medical Center, La Jolla, CA, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Division of Hematology Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
authors.forename: M U
authors.initials: MU
authors.lastname: Callaghan
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Division of Hematology Oncology, Children's Hospital of Michigan, Detroit, MI, USA Department of Otolaryngology, Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA rkaufman@sanfordburnham.org afribley@med.wayne.edu.
authors.forename: A M
authors.initials: AM
authors.lastname: Fribley
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016466:CHO Cells; D002193:Cantharidin / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D057166:High-Throughput Screening Assays; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics; D051379:Mice; D009062:Mouth Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D051742:Transcription Factor CHOP / Q000235:genetics; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; C081452:Atf4 protein, mouse; D019086:Bridged Bicyclo Compounds, Heterocyclic; C497250:Ddit3 protein, mouse; D034741:RNA, Small Interfering; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C069741:norcantharidin; D001191:Arylamine N-Acetyltransferase; D002193:Cantharidin
keywords: ATF4; CHOP; UPR; cantharide; chemotherapy; natural products