尽管越来越多的研究证明纳米羟基磷灰石（n-HA）具有特定的抗肿瘤作用，但其潜在机制仍不清楚。内质网 (ER) 和线粒体是细胞内 Ca2 稳态的两个关键参与者，都需要 Ca2 参与。此外，ER-线粒体相互作用协调细胞Ca2+稳态的维持，以防止Ca2+过量产生任何负面后果，因此需要深入研究n-HA对其的影响。在本研究中，我们制造了针状n-HA，从细胞和分子角度研究其抗肿瘤效果及其潜在机制。体外实验数据表明，在n-HA的帮助下，胶质瘤细胞的生长和侵袭明显减少。有趣的是，n-HA 处理后，ER 应激生物标志物（GRP78、p-IRE1、p-PERK、PERK 和 ATF6）的表达均上调，同时促凋亡转录因子 CHOP 被激活。显示 n-HA 产生的 ER 应激触发细胞凋亡。此外，细胞内活性氧表达水平的增加和线粒体膜去极化，以及下游细胞凋亡信号的激活，进一步证明了n-HA通过诱导线粒体损伤而诱导Ca2+超载的促凋亡作用。体内数据提供了额外的证据，证明n-HA引起细胞内ER应激和线粒体损伤，并有效抑制神经胶质瘤的生长。总的来说，这项工作表明，n-HA 共同激活的细胞内 ER 应激和线粒体损伤是癌细胞凋亡的关键触发因素，为 ER-线粒体靶向抗肿瘤治疗提供了新的视角。© 作者 2024。牛津大学出版大学出版社。

Despite a growing body of studies demonstrating the specific anti-tumor effect of nano-hydroxyapatite (n-HA), the underlying mechanism remained unclear. Endoplasmic reticulum (ER) and mitochondria are two key players in intracellular Ca2+ homeostasis and both require Ca2+ to participate. Moreover, the ER-mitochondria interplay coordinates the maintenance of cellular Ca2+ homeostasis to prevent any negative consequences from excess of Ca2+, hence there needs in-depth study of n-HA effect on them. In this study, we fabricated needle-like n-HA to investigate the anti-tumor effectiveness as well as the underlying mechanisms from cellular and molecular perspectives. Data from in vitro experiments indicated that the growth and invasion of glioma cells were obviously reduced with the aid of n-HA. It is interesting to note that the expression of ER stress biomarkers (GRP78, p-IRE1, p-PERK, PERK, and ATF6) were all upregulated after n-HA treatment, along with the activation of the pro-apoptotic transcription factor CHOP, showing that ER stress produced by n-HA triggered cell apoptosis. Moreover, the increased expression level of intracellular reactive oxygen species and the mitochondrial membrane depolarization, as well as the downstream cell apoptotic signaling activation, further demonstrated the pro-apoptotic roles of n-HA induced Ca2+ overload through inducing mitochondria damage. The in vivo data provided additional evidence that n-HA caused ER stress and mitochondria damage in cells and effectively restrain the growth of glioma tumors. Collectively, the work showed that n-HA co-activated intracellular ER stress and mitochondria damage are critical triggers for cancer cells apoptosis, offering fresh perspectives on ER-mitochondria targeted anti-tumor therapy.© The Author(s) 2024. Published by Oxford University Press.