Dravecka Maria, Mikkola Ingvild, Johansen Terje, Seternes Ole Morten, Mejlvang Jakob
Cell Signalling and Targeted therapy, Department of Pharmacy, UiT The Arctic University of Norway, Tromsø, Norway.
Autophagy Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway.
Cell Death Discov. 2025 Apr 3;11(1):137. doi: 10.1038/s41420-025-02440-w.
Ammonia is a natural waste product of cellular metabolism which, through its lysosomotropic ability, can have detrimental effects on various cellular functions. Increased levels of ammonia were recently detected in the interstitial fluid of various tumours, substantiating that high ammonia concentrations are a pathophysiological condition in the tumour microenvironment, alongside hypoxia and acidosis. Since little is known about how cancer cells respond to elevated levels of ammonia in the tumour microenvironment, we investigated how a panel of cancer cell lines derived from solid tumours behaved when exposed to increasing concentrations of ammonia. We found that ammonia represses cell growth, induces genome instability, and inhibits lysosome-mediated proteolysis in a dose-dependent manner. Unexpectedly, we also found that small fluctuations in the pH of the extracellular environment, had a significant impact on the cytotoxic effects of ammonia. In summary, our data show that the balance of pH and ammonia within the interstitial fluids of cancerous tumours significantly impacts the behaviour and fate of cells residing in the tumour microenvironment.
氨是细胞代谢产生的天然废物，凭借其溶酶体亲和性，可对多种细胞功能产生有害影响。最近在各种肿瘤的间质液中检测到氨水平升高，这证实高氨浓度是肿瘤微环境中的一种病理生理状态，与缺氧和酸中毒并存。由于对癌细胞如何应对肿瘤微环境中升高的氨水平知之甚少，我们研究了一组源自实体瘤的癌细胞系在暴露于不断增加浓度的氨时的行为。我们发现氨以剂量依赖的方式抑制细胞生长、诱导基因组不稳定并抑制溶酶体介导的蛋白水解。出乎意料的是，我们还发现细胞外环境pH值的小波动对氨的细胞毒性作用有显著影响。总之，我们的数据表明，癌瘤间质液中pH值和氨的平衡显著影响肿瘤微环境中细胞的行为和命运。
