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Celecoxib and sulindac sulfide elicit anticancer effects on PIK3CA-mutated head and neck cancer cells through endoplasmic reticulum stress, reactive oxygen species, and mitochondrial dysfunction

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dc.contributor.authorNguyen, NTT-
dc.contributor.authorLee, SY-
dc.date.accessioned2024-06-19T07:07:09Z-
dc.date.available2024-06-19T07:07:09Z-
dc.date.issued2024-
dc.identifier.issn0006-2952-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/32557-
dc.description.abstractGain-of-function mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha gene (PIK3CA) is a significant factor in head and neck cancer (HNC). Patients with HNC harboring PIK3CA mutations receive therapeutic benefits from the use of non-steroidal anti-inflammatory drugs (NSAIDs). However, the molecular mechanisms underlying these effects remain unknown. Here, we examined the Detroit562 and FaDu cell lines as HNC models with and without a hyperactive PIK3CA mutation (H1047R), respectively, regarding their possible distinct responses to the NSAIDs celecoxib and sulindac sulfide (SUS). Detroit562 cells exhibited relatively high PI3K/Akt pathway-dependent cyclooxygenase-2 (COX-2) expression, associated with cell proliferation. Celecoxib treatment restricted cell proliferation and upregulated endoplasmic reticulum (ER) stress-related markers, including GRP78, C/EBP-homologous protein, activating transcription factor 4, death receptor 5, and reactive oxygen species (ROS). These effects were much stronger in Detroit562 cells than in FaDu cells and were largely COX-2-independent. SUS treatment yielded similar results. Salubrinal (an ER stress inhibitor) and N-acetyl-L-cysteine (a ROS scavenger) prevented NSAID-induced ROS generation and ER stress, respectively, indicating crosstalk between ER and oxidative stress. In addition, celecoxib and/or SUS elevated cleaved caspase-3 levels, Bcl-2-associated X protein/Bcl-2-interacting mediator of cell death expression, and mitochondrial damage, which was more pronounced in Detroit562 than in FaDu cells. Salubrinal and N-acetyl-L-cysteine attenuated celecoxib-induced mitochondrial dysfunction. Collectively, our results suggest that celecoxib and SUS efficiently suppress activating PIK3CA mutation-harboring HNC progression by inducing ER and oxidative stress and mitochondrial dysfunction, leading to apoptotic cell death, further supporting NSAID treatment as a useful strategy for oncogenic PIK3CA-mutated HNC therapy.-
dc.language.isoen-
dc.subject.MESHAntineoplastic Agents-
dc.subject.MESHCelecoxib-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHCell Proliferation-
dc.subject.MESHClass I Phosphatidylinositol 3-Kinases-
dc.subject.MESHEndoplasmic Reticulum Chaperone BiP-
dc.subject.MESHEndoplasmic Reticulum Stress-
dc.subject.MESHHead and Neck Neoplasms-
dc.subject.MESHHumans-
dc.subject.MESHMitochondria-
dc.subject.MESHMutation-
dc.subject.MESHReactive Oxygen Species-
dc.subject.MESHSulindac-
dc.titleCelecoxib and sulindac sulfide elicit anticancer effects on PIK3CA-mutated head and neck cancer cells through endoplasmic reticulum stress, reactive oxygen species, and mitochondrial dysfunction-
dc.typeArticle-
dc.identifier.pmid38641308-
dc.subject.keywordCelecoxib-
dc.subject.keywordER stress-
dc.subject.keywordHead and neck cancer-
dc.subject.keywordPIK3CA mutation-
dc.subject.keywordReactive oxygen species-
dc.subject.keywordSulindac sulfide-
dc.contributor.affiliatedAuthorLee, SY-
dc.type.localJournal Papers-
dc.identifier.doi10.1016/j.bcp.2024.116221-
dc.citation.titleBiochemical pharmacology-
dc.citation.volume224-
dc.citation.date2024-
dc.citation.startPage116221-
dc.citation.endPage116221-
dc.identifier.bibliographicCitationBiochemical pharmacology, 224. : 116221-116221, 2024-
dc.embargo.liftdate9999-12-31-
dc.embargo.terms9999-12-31-
dc.identifier.eissn1873-2968-
dc.relation.journalidJ000062952-
Appears in Collections:
Journal Papers > Research Organization > Institute for Medical Sciences
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