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Compressive constraint promotes the cytotoxicity of PI3K signal targeted therapies in breast and pancreatic cancer cells
bioRxiv - Cancer Biology Pub Date : 2023-06-13 , DOI: 10.1101/2021.10.18.464825
M. Di-Luoffo , M. Delarue , J. Guillermet-Guibert

Context: Mechanical stresses, including compressive stress, arise during cancer progression. The rapid tumor growth and massive extra-cellular matrix remodeling of breast and pancreatic cancers explain the high intensity of compressive constraint in those pathologies. However, the transduction of compressive constraint into biochemical signals in cancer cells and the sensitivity of compressed cancer cells to therapies that target those signals remains poorly known. Results: We tested the effect of constant and high intensity 2D compression in four cancer cell lines where pharmacological and genetic PI3K inactivation alone decreased cell confluency. PI3K inhibition associated or not with compression accentuated cell confluency decrease and induced cell death, showing the importance of PI3K for cell survival under compression. Mechanistically, unbiased analysis identified that compression induced overexpression of PI3K isoforms and PI3K activation. Transcriptional effects of PI3K inhibition and compression converge to control mRNA and protein levels of an autophagy regulator GABARAP. PI3K inhibition and compression blocked autophagy, as assessed by accumulation of p62/SQSTM1 autophagosome cargo and decreased LC3B-II-mediated autophagy flux. Conclusion: This study provides evidence for the role of PI3K in compression mechanotransduction. The balance between cell death and autophagy mediated by GABARAP level may sustain cell survival in compressive stress environment.

中文翻译:

压缩约束促进 PI3K 信号靶向疗法在乳腺癌和胰腺癌细胞中的细胞毒性

背景:在癌症进展过程中会出现机械应力,包括压缩应力。乳腺癌和胰腺癌的快速肿瘤生长和大量细胞外基质重塑解释了这些病理学中压缩约束的高强度。然而,压缩约束转导为癌细胞中的生化信号以及压缩癌细胞对靶向这些信号的疗法的敏感性仍然鲜为人知。结果:我们在四种癌细胞系中测试了恒定和高强度 2D 压缩的效果,其中单独的药理学和遗传 PI3K 失活会降低细胞汇合度。与压缩相关或不相关的 PI3K 抑制会加剧细胞汇合减少并诱导细胞死亡,显示 PI3K 对压缩下细胞存活的重要性。从机械上讲,无偏分析确定压缩诱导 PI3K 亚型和 PI3K 激活的过度表达。PI3K 抑制和压缩的转录效应会聚以控制自噬调节剂 GABARAP 的 mRNA 和蛋白质水平。PI3K 抑制和压缩阻断了自噬,这是通过 p62/SQSTM1 自噬体货物的积累和 LC3B-II 介导的自噬通量降低来评估的。结论:本研究为 PI3K 在压缩机械传导中的作用提供了证据。由 GABARAP 水平介导的细胞死亡和自噬之间的平衡可以维持细胞在压力环境中的存活。PI3K 抑制和压缩的转录效应会聚以控制自噬调节剂 GABARAP 的 mRNA 和蛋白质水平。PI3K 抑制和压缩阻断了自噬,这是通过 p62/SQSTM1 自噬体货物的积累和 LC3B-II 介导的自噬通量降低来评估的。结论:本研究为 PI3K 在压缩机械传导中的作用提供了证据。由 GABARAP 水平介导的细胞死亡和自噬之间的平衡可以维持细胞在压力环境中的存活。PI3K 抑制和压缩的转录效应会聚以控制自噬调节剂 GABARAP 的 mRNA 和蛋白质水平。PI3K 抑制和压缩阻断了自噬,这是通过 p62/SQSTM1 自噬体货物的积累和 LC3B-II 介导的自噬通量降低来评估的。结论:本研究为 PI3K 在压缩机械传导中的作用提供了证据。由 GABARAP 水平介导的细胞死亡和自噬之间的平衡可以维持细胞在压力环境中的存活。
更新日期:2023-06-15
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