Inhibition of CaMKIIα Activity Enhances Antitumor Effect of Fullerene C60 Nanocrystals by Suppression of Autophagic Degradation
Year: 2019
Type: article
Abstract: Fullerene C60 nanocrystals (nano-C60) possess various attractive bioactivities, including autophagy induction and calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) activation. CaMKIIα is a multifunctional protein kinase involved in many cellular processes including tumor progression; however, the biological effects of CaMKIIα activity modulated by nano-C60 in tumors have not been reported, and the relationship between CaMKIIα activity and autophagic degradation remains unclear. Herein, nano-C60 is demonstrated to elicit reactive oxygen species (ROS)-dependent cytotoxicity and persistent activation of CaMKIIα in osteosarcoma (OS) cells. CaMKIIα activation, in turn, produces a protective effect against cytotoxicity from nano-C60 itself. Inhibition of CaMKIIα activity by either the chemical inhibitor KN-93 or CaMKIIα knockdown dramatically promotes the anti-OS effect of nano-C60. Moreover, inhibition of CaMKIIα 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 CaMKIIα inhibition, along with the suppression of autophagic degradation, presents a promising strategy for improving the antitumor efficacy of nano-C60.
Source: Advanced Science
Authors: Jing Xu, Hongsheng Wang, Yi Hu, Yu Shrike Zhang, Longping Wen, Fei Yin, Zhuoying Wang, Yingchao Zhang, Suoyuan Li, Yanyan Miao, Binhui Lin, Dongqing Zuo, Gangyang Wang, Min Mao, Tao Zhang, Jianxun Ding, Yingqi Hua, Zhengdong Cai
Institutions: Shanghai Jiao Tong University, Shanghai First People's Hospital, University of Science and Technology of China, Hefei National Center for Physical Sciences at Nanoscale, Brigham and Women's Hospital, Harvard University, South China University of Technology, Sun Yat-sen University, Chinese Academy of Sciences, Changchun Institute of Applied Chemistry
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $5,000
OpenAlex ID: W2913307374