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阿司匹林对Ⅵ型磷脂酶A2的抑制作用在AAM途径下调的龈颊鳞状细胞癌中诱导合成致死效应。

Aspirin Inhibition of Group VI Phospholipase A2 Induces Synthetic Lethality in AAM Pathway Down-Regulated Gingivobuccal Squamous Carcinoma.

作者信息

Pansare Kshama, Mohanty Bhabani, Dhotre Ranjeeta, Pettiwala Aafrin M, Parab Saili, Gupta Neha, Gera Poonam, Gardi Nilesh, Dugge Rucha, Sahu Priyanka, Alhans Ruby, Kowtal Pradnya, Chaudhari Pradip, Sarin Rajiv

机构信息

ICGC Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India.

Small Animal Imaging Facility, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India.

出版信息

Cells. 2021 Dec 30;11(1):123. doi: 10.3390/cells11010123.

DOI:10.3390/cells11010123
PMID:35011685
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8750243/
Abstract

BACKGROUND

To elucidate the role of iPLA2/PLA2G6 in gingivobuccal squamous cell carcinoma (GB-SCC) and to ascertain the synthetic lethality-based chemoprevention role of aspirin in arachidonic acid metabolism (AAM) pathway down-regulated GB-SCC.

METHODS

The in vitro efficacy of aspirin on GB-SCC cells (ITOC-03 and ITOC-04) was assessed by cell proliferation, colony formation, apoptosis, cell migration, cell cycle assay and RNA-seq, while inhibition of PLA2G6 and AAM pathway components was affirmed by qPCR, Western blot and immunofluorescence staining. The in vivo effect of aspirin was evaluated using NOD-SCID mice xenografts and immunohistochemical analysis.

RESULTS

We found that aspirin, which has been reported to act through the COX pathway, is inhibiting PLA2G6, and thereby the COX and LOX components of the AAM pathway. The findings were validated using PLA2G6 siRNA and immunohistochemical marker panel. Moreover, a pronounced effect in ITOC-04 cells and xenografts implied aspirin-induced synthetic lethality in the AAM pathway down-regulated GB-SCC.

CONCLUSIONS

This study reveals that aspirin induces the anti-tumor effect by a previously unrecognized mechanism of PLA2G6 inhibition. In addition, the effect of aspirin is influenced by the baseline AAM pathway status and could guide precision prevention clinical trials of AAM pathway inhibitors.

摘要

背景

阐明iPLA2/PLA2G6在龈颊鳞状细胞癌（GB-SCC）中的作用，并确定阿司匹林在花生四烯酸代谢（AAM）途径下调的GB-SCC中基于合成致死性的化学预防作用。

方法

通过细胞增殖、集落形成、凋亡、细胞迁移、细胞周期分析和RNA测序评估阿司匹林对GB-SCC细胞（ITOC-03和ITOC-04）的体外疗效，同时通过qPCR、蛋白质印迹和免疫荧光染色确认对PLA2G6和AAM途径成分的抑制作用。使用NOD-SCID小鼠异种移植和免疫组织化学分析评估阿司匹林的体内作用。

结果

我们发现，据报道通过COX途径发挥作用的阿司匹林正在抑制PLA2G6，从而抑制AAM途径的COX和LOX成分。使用PLA2G6 siRNA和免疫组织化学标志物组验证了这些发现。此外，在ITOC-04细胞和异种移植中的显著作用暗示阿司匹林在AAM途径下调的GB-SCC中诱导了合成致死性。

结论

本研究表明，阿司匹林通过一种以前未被认识的抑制PLA2G6的机制诱导抗肿瘤作用。此外，阿司匹林的作用受基线AAM途径状态的影响，并可为AAM途径抑制剂的精准预防临床试验提供指导。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/b33b7b0d71a9/cells-11-00123-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/2ce22d592bd1/cells-11-00123-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/676b535eb745/cells-11-00123-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/12c6fd2e286f/cells-11-00123-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/a3bc046fd899/cells-11-00123-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/9acdcfe8a4ab/cells-11-00123-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/b33b7b0d71a9/cells-11-00123-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/2ce22d592bd1/cells-11-00123-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/676b535eb745/cells-11-00123-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/12c6fd2e286f/cells-11-00123-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/a3bc046fd899/cells-11-00123-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/9acdcfe8a4ab/cells-11-00123-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/707e/8750243/b33b7b0d71a9/cells-11-00123-g006.jpg

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