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.

Erin B. Taylor,Emad Kandil,Zakaria Y. Abd Elmageed,Abdulhadi A. Alamodi,Mohamed Hassan,Srinivasan Vijaykumar,Matthias Hannig,Abdulaziz Alkhateeb,Sofie Y. Hassan,Youssef Haikel,Simeon Santourlidis,Paul L. Friedlander,Denis Selimovic,Siraj M. El Jamal

doi:10.1186/s13008-016-0023-4

Abstract

BackgroundTumor 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.ResultsIFNγ 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.ConclusionIn 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.

Highlights

Tumor response to immunotherapy is the consequence of a concerted crosstalk between cytokines and effector cells
We analysed the expression of molecular markers of apoptosis, including cytochrome c, caspase-9, caspase-3, and poly ADP ribose polymerase (PARP) in head and neck squamous cell carcinoma (HNSCC) cells
We investigated whether interferon gamma (IFNγ)-induced activation of apoptosis signal-regulating kinase 1 (ASK1)-jun-N-terminal kinase (JNK), ASK1-p38 or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways is associated with the enhancement of the DNA-binding activity of the transcription factors activator protein 1 (AP-1), p53, activating transcription factor 2 (ATF-2) and NF-κB

Summary

Introduction

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. 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. Interferon gamma (IFNγ) is one of the central cytokines that coordinates tumor immune responses and the associated biological consequences [2]. Because the current reported studies on the molecular action of IFN-γ in tumor cells are merely speculative, the aim of the present study is to elucidate, in detail, the mechanisms which are responsible for the modulation of IFN-γ-induced effects on HNSCC cells

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