title: Interferon gamma-induced apoptosis of head and neck squamous cell carcinoma is connected to indoleamine-2,3-dioxygenase via mitochondrial and ER stress-associated pathways.
abstract: BACKGROUND
  Tumor response to immunotherapy is the consequence of a concerted crosstalk between cytokines and effector cells. Interferon gamma (IFNγ) is one of the common cytokines coordinating tumor immune response and the associated biological consequences. Although the role of IFNγ in the modulation of tumor immunity has been widely documented, the mechanisms regulating IFNγ-induced cell death, during the course of immune therapy, is not described in detail.
  
  
  RESULTS
  IFNγ triggered apoptosis of CLS-354 and RPMI 2650 cells, enhanced the protein expression and activation of indoleamine 2,3-dioxygenase (IDO), and suppressed the basal expression of heme oxygenase-1(HO-1). Interestingly, IFNγ induced the loss of mitochondrial membrane potential (Δψm) and increased accumulation of reactive oxygen species (ROS). The cytokine also induced the activation of Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT)1, apoptosis signal-regulating kinase 1 (ASK1), p38, c-jun-N-terminal kinase (JNK) and NF-κB pathways and the transcription factors STAT1, interferon regulatory factor 1 (IRF1), AP-1, ATF-2, NF-κB and p53, and expression of Noxa protein. Furthermore, IFNγ was found to trigger endoplasmic reticulum (ER) stress as evidenced by the cleavage of caspase-4 and activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring-1α (IRE1α) pathways. Using specific inhibitors, we identified a potential role for IDO as apoptotic mediator in the regulation of IFNγ-induced apoptosis of head and neck squamous cell carcinoma (HNSCC) cells via Noxa-mediated mitochondrial dysregulation and ER stress.
  
  
  CONCLUSIONS
  In addition to the elucidation of the role of IDO in the modulation of apoptosis, our study provides new insights into the molecular mechanisms of IFNγ-induced apoptosis of HNSCC cells during the course of immune therapy.
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216 USA.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: El Jamal
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216 USA.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Taylor
authors.affiliation: Departments of Surgery, Tulane University School of Medicine, New Orleans, LA 70112 USA.
authors.forename: Zakaria Y
authors.initials: ZY
authors.lastname: Abd Elmageed
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216 USA.
authors.forename: Abdulhadi A
authors.initials: AA
authors.lastname: Alamodi
authors.affiliation: Clinic of Operative Dentistry, Periodontology and Preventive Dentistry, Saarland University, Kirrberger Str. 100, 66421 Homburg/Saar, Germany ; Division of Oral Health Science, Department of Restorative Dentistry, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Denis
authors.initials: D
authors.lastname: Selimovic
authors.affiliation: Clinic of Dermatology, University Hospital of Aachen, Puwelstrasse 30, Aachen, Germany ; College of Medicine, King Faisal University, Alhofuf, Saudi Arabia.
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Alkhateeb
authors.affiliation: Clinic of Operative Dentistry, Periodontology and Preventive Dentistry, Saarland University, Kirrberger Str. 100, 66421 Homburg/Saar, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hannig
authors.affiliation: Clinic of Dermatology, University Hospital of Aachen, Puwelstrasse 30, Aachen, Germany.
authors.forename: Sofie Y
authors.initials: SY
authors.lastname: Hassan
authors.affiliation: Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, University Hospital of Duesseldorf, Heinrich-Heine-University of Duesseldorf, Mooren Str.5, 40225 Duesseldorf, Germany.
authors.forename: Simeon
authors.initials: S
authors.lastname: Santourlidis
authors.affiliation: Departments of Surgery, Tulane University School of Medicine, New Orleans, LA 70112 USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Friedlander
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France ; Department of Operative Dentistry and Endodontics, Dental Faculty, University of Strasbourg, 67000 Strasbourg, France.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Haikel
authors.affiliation: Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS 39216 USA ; Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216 USA.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Vijaykumar
authors.affiliation: Departments of Surgery, Tulane University School of Medicine, New Orleans, LA 70112 USA.
authors.forename: Emad
authors.initials: E
authors.lastname: Kandil
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216 USA ; Clinic of Operative Dentistry, Periodontology and Preventive Dentistry, Saarland University, Kirrberger Str. 100, 66421 Homburg/Saar, Germany ; Institut National de la Santé et de la Recherche Médicale, University of Strasbourg, 67000 Strasbourg, France ; Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216 USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hassan
keywords: FN-γ; HNSCC; HO-1; IDO; JAK; STAT1