Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.redox.2021.102193
Title: TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3
Authors: Raman, Deepika
Tay, Patricia 
Hirpara, Jayshree L 
Liu, Dan 
Pervaiz, Shazib 
Keywords: NPC
TRAIL
Peroxynitrite
Caspase-3
TMTC2
Issue Date: 1-Dec-2021
Publisher: ELSEVIER
Citation: Raman, Deepika, Tay, Patricia, Hirpara, Jayshree L, Liu, Dan, Pervaiz, Shazib (2021-12-01). TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3. REDOX BIOLOGY 48. ScholarBank@NUS Repository. https://doi.org/10.1016/j.redox.2021.102193
Abstract: Aims: Preferential expression of receptors for TNF-family related apoptosis inducing ligand (TRAIL), DR4 and DR5 makes TRAIL an attractive anti-cancer therapeutic. However, the efficacy of targeting death receptors has not been extensively studied in nasopharyngeal cancer (NPC). Here we investigated TRAIL sensitivity and its underlying mechanism in NPC cell lines, and assessed the potential of TRAIL as a therapeutic option against NPC. Results: Using two established NPC cell lines, we report the expression of DR4 and DR5, which respond to TRAIL ligation by triggering efficient Type II apoptosis. Mechanistically, early activation of caspase-3 and its membrane recruitment is identified in NPC cell lines, which is associated with, hitherto unreported, interaction with transmembrane and tetratricopeptide repeat containing 2 (TMTC2) in the lipid raft domains. TMTC2 expression is induced upon exposure to TRAIL and involves intracellular increase in peroxynitrite (ONOO−) production. While ONOO− increase is downstream of caspase-8 activation, it is involved in the upregulation of TMTC2, gene knockdown of which abrogated TRAIL-induced apoptotic execution. Bioinformatics analyses also provide evidence for a strong correlation between TMTC2 and DR4 or caspase-3 as well as a significantly better disease-free survival in patients with high TMTC2 expression. Innovation and conclusion: Collectively, redox-dependent execution of NPC cells upon ligation of TRAIL receptors reintroduces the possible therapeutic use of TRAIL in NPC as well as underscores the potential of using TMTC2 as a biomarker of TRAIL sensitivity.
Source Title: REDOX BIOLOGY
URI: https://scholarbank.nus.edu.sg/handle/10635/224516
ISSN: 2213-2317
DOI: 10.1016/j.redox.2021.102193
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