Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
School of Pharmacy, Eastern Asia University, Pathum Thani, 12110, Thailand.
Biol Res. 2023 Aug 5;56(1):44. doi: 10.1186/s40659-023-00456-z.
Malignant cells adopt anoikis resistance to survive anchorage-free stresses and initiate cancer metastasis. It is still unknown how varying periods of anchorage loss contribute to anoikis resistance, cell migration, and metabolic reprogramming of cancerous cells.
Our study demonstrated that prolonging the anchorage-free lifetime of non-small-cell lung cancer NCI-H460 cells for 7 days strengthened anoikis resistance, as shown by higher half-life and capability to survive and grow without anchorage, compared to wild-type cells or those losing anchorage for 3 days. While the prolonged anchorage-free lifetime was responsible for the increased aggressive feature of survival cells to perform rapid 3-dimensional migration during the first 3 h of a transwell assay, no significant influence was observed with 2-dimensional surface migration detected at 12 and 24 h by a wound-healing method. Metabolomics analysis revealed significant alteration in the intracellular levels of six (oxalic acid, cholesterol, 1-ethylpyrrolidine, 1-(3-methylbutyl)-2,3,4,6-tetramethylbenzene, β-alanine, and putrescine) among all 37 identified metabolites during 7 days without anchorage. Based on significance values, enrichment ratios, and impact scores of all metabolites and their associated pathways, three principal metabolic activities (non-standard amino acid metabolism, cell membrane biosynthesis, and oxidative stress response) offered potential links with anoikis resistance.
These findings further our insights into the evolution of anoikis resistance in lung cancer cells and identify promising biomarkers for early lung cancer diagnosis.
恶性细胞通过抗失巢凋亡来适应无锚定压力并启动癌症转移。目前尚不清楚不同的锚定损失时间如何促进抗失巢凋亡、细胞迁移和癌变细胞的代谢重编程。
我们的研究表明，延长非小细胞肺癌 NCI-H460 细胞的无锚定寿命 7 天，与野生型细胞或失去锚定 3 天的细胞相比，增强了抗失巢凋亡能力，表现为半衰期更长、无需锚定即可存活和生长的能力。虽然延长的无锚定寿命导致存活细胞的侵袭性特征增加，使其能够在 Transwell 测定的前 3 小时内快速进行 3 维迁移，但通过划痕愈合法在 12 和 24 小时检测到的 2 维表面迁移没有观察到显著影响。代谢组学分析显示，在无锚定的 7 天内，37 种鉴定代谢物中有 6 种（草酸、胆固醇、1-乙基吡咯烷、1-（3-甲基丁基）-2,3,4,6-四甲基苯、β-丙氨酸和腐胺）的细胞内水平发生了显著变化。基于所有代谢物及其相关途径的显著性值、富集比和影响分数，三种主要代谢活性（非标准氨基酸代谢、细胞膜生物合成和氧化应激反应）为抗失巢凋亡提供了潜在的联系。
这些发现进一步深入了解了肺癌细胞抗失巢凋亡的演变，并确定了早期肺癌诊断的有前途的生物标志物。
