Wang Yifu, Wu Hongfeng, Chen Zhu, Cao Jun, Zhu Xiangdong, Zhang Xingdong
National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, P. R. China.
College of Biomedical Engineering, Sichuan University, Chengdu 610064, P. R. China.
Regen Biomater. 2024 Apr 18;11:rbae038. doi: 10.1093/rb/rbae038. eCollection 2024.
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 Ca homeostasis and both require Ca to participate. Moreover, the ER-mitochondria interplay coordinates the maintenance of cellular Ca homeostasis to prevent any negative consequences from excess of Ca, 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 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 Ca overload through inducing mitochondria damage. The 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.
尽管越来越多的研究表明纳米羟基磷灰石（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）和线粒体是细胞内钙稳态的两个关键参与者，两者都需要钙参与。此外，内质网-线粒体相互作用协调细胞钙稳态的维持，以防止钙过量产生的任何负面后果，因此需要深入研究n-HA对它们的影响。在本研究中，我们制备了针状n-HA，从细胞和分子角度研究其抗肿瘤效果及其潜在机制。实验数据表明，在n-HA的作用下，胶质瘤细胞的生长和侵袭明显减少。值得注意的是，n-HA处理后内质网应激生物标志物（GRP78、p-IRE1、p-PERK、PERK和ATF6）的表达均上调，同时促凋亡转录因子CHOP激活，表明n-HA产生的内质网应激触发了细胞凋亡。此外，细胞内活性氧水平升高、线粒体膜去极化以及下游细胞凋亡信号激活，进一步证明了n-HA通过诱导线粒体损伤导致钙超载从而发挥促凋亡作用。这些数据提供了额外的证据，表明n-HA在细胞中引起内质网应激和线粒体损伤，并有效抑制胶质瘤肿瘤的生长。总的来说，这项工作表明n-HA共同激活细胞内内质网应激和线粒体损伤是癌细胞凋亡的关键触发因素，为内质网-线粒体靶向抗肿瘤治疗提供了新的视角。
