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Adv Sci (Weinh). 2019 Feb 10;6(8):1801233. doi: 10.1002/advs.201801233. eCollection 2019 Apr 17.

Inhibition of CaMKIIα Activity Enhances Antitumor Effect of Fullerene C60 Nanocrystals by Suppression of Autophagic Degradation.

Author information

1
Department of Orthopedics Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai Bone Tumor Institution 100 Haining Street Shanghai 200080 P. R. China.
2
Shanghai Bone Tumor Institution 100 Haining Street Shanghai 200080 P. R. China.
3
Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences University of Science and Technology of China 96 Jinzhai Street Hefei 230026 P. R. China.
4
Division of Engineering in Medicine Department of Medicine Brigham and Women's Hospital Harvard Medical School 65 Landsdowne Street Cambridge MA 02139 USA.
5
School of Medicine South China University of Technology Nanobio Laboratory Institutes for Life Sciences South China University of Technology 381 Wushan Street Guangzhou 510006 P. R. China.
6
Key Laboratory of Gene Engineering of the Ministry of Education State Key Laboratory of Biocontrol School of Life Sciences Sun Yat-sen University 135 West Xingang Street Guangzhou 510275 P. R. China.
7
Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences 5625 Renmin Street Changchun 130022 P. R. China.

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.

KEYWORDS:

autophagic degradation; autophagy; calcium/calmodulin‐dependent protein kinase IIα; fullerene C60 nanocrystals; osteosarcoma therapy

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