Inhibition of CaMKIIα Activity Enhances Antitumor Effect of Fullerene C60 Nanocrystals by Suppression of Autophagic Degradation
Inhibition of CaMKIIα Activity Enhances Antitumor Effect of Fullerene C60 Nanocrystals by Suppression of Autophagic Degradation
复制标题
抑制 CaMKIIα 活性通过抑制自噬降解增强富勒烯 C60 纳米晶体的抗肿瘤作用
DOI：
10.1002/advs.201801233
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发表时间：
2019-04-17
期刊：
影响因子：
15.1
通讯作者：
Cai, Zhengdong
中科院分区：
文献类型：
--
作者：
Xu, Jing;Wang, Hongsheng;Cai, Zhengdong
富勒烯C60纳米晶体（nano-C60）具有多种吸引人的生物活性，包括自噬诱导和钙/钙调素依赖性蛋白激酶II α (CaMKII α)活化。CaMKII α是一种多功能蛋白激酶，参与包括肿瘤进展在内的许多细胞过程；然而，纳米c60调节CaMKII α活性在肿瘤中的生物学效应尚未见报道，CaMKII α活性与自噬降解之间的关系尚不清楚。在此，纳米c60被证明在骨肉瘤（OS）细胞中引起活性氧（ROS）依赖的细胞毒性和CaMKII α的持续激活。CaMKII α激活，反过来，对纳米c60本身的细胞毒性产生保护作用。化学抑制剂k -93或CaMKII α敲低对CaMKII α活性的抑制均可显著促进nanoC60的抗os作用。此外，抑制CaMKII α活性会导致溶酶体碱化和扩增，损害溶酶体的降解功能，导致自噬体积聚。重要的是，过度的自噬体积累和自噬降解阻断在kn -93增强的os细胞死亡中发挥重要作用。在异种移植os的小鼠模型中进一步揭示了KN-93和纳米c60的协同抗os作用。结果表明，抑制CaMKII α，同时抑制自噬降解，是提高纳米c60抗肿瘤效果的一种很有前景的策略。
Fullerene C60 nanocrystals (nano-C60) possess various attractive bioactivities, including autophagy induction and calcium/calmodulin-dependent protein kinase II alpha (CaMKII alpha) activation. CaMKII alpha is a multifunctional protein kinase involved in many cellular processes including tumor progression; however, the biological effects of CaMKII alpha activity modulated by nano-C60 in tumors have not been reported, and the relationship between CaMKII alpha activity and autophagic degradation remains unclear. Herein, nano-C60 is demonstrated to elicit reactive oxygen species (ROS)-dependent cytotoxicity and persistent activation of CaMKII alpha in osteosarcoma (OS) cells. CaMKII alpha activation, in turn, produces a protective effect against cytotoxicity from nano-C60 itself. Inhibition of CaMKII alpha activity by either the chemical inhibitor KN-93 or CaMKII alpha knockdown dramatically promotes the anti-OS effect of nanoC60. Moreover, inhibition of CaMKII alpha activity causes lysosomal alkalinization and enlargement, and impairs the degradation function of lysosomes, leading to autophagosome accumulation. Importantly, excessive autophagosome accumulation and autophagic degradation blocking are shown to play an important role in KN-93-enhanced-OS cell death. The synergistic anti-OS efficacy of KN-93 and nano-C60 is further revealed in an OS-xenografted murine model. The results demonstrate that CaMKII alpha inhibition, along with the suppression of autophagic degradation, presents a promising strategy for improving the antitumor efficacy of nano-C60.