The inhibitor of calcium/calmodulin-dependent protein kinase II KN93 attenuates bone cancer pain via inhibition of KIF17/NR2B trafficking in mice.
The N-methyl-d-aspartate receptor (NMDAR) containing subunit 2B (NR2B) is critical for the regulation of nociception in bone cancer pain, although the precise molecular mechanisms remain unclear. KIF17, a kinesin motor, plays a key role in the dendritic transport of NR2B. The up-regulation of NR2B and KIF17 transcription results from an increase in phosphorylated cAMP-response element-binding protein (CREB), which is activated by calcium/calmodulin-dependent protein kinase II (CaMKII). In this study, we hypothesized that CaMKII-mediated KIF17/NR2B trafficking may contribute to bone cancer pain. Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce progressive bone cancer-related pain behaviors. The expression of spinal t-CaMKII, p-CaMKII, NR2B and KIF17 after inoculation was also evaluated. These results showed that inoculation of osteosarcoma cells induced progressive bone cancer pain and resulted in a significant up-regulation of p-CaMKII, NR2B and KIF17 expression after inoculation. Intrathecal administration of KN93, a CaMKII inhibitor, down-regulated these three proteins and attenuated bone cancer pain in a dose- and time-dependent manner. These findings indicated that CaMKII-mediated KIF17/NR2B trafficking may contribute to bone cancer pain, and inhibition of CaMKII may be a useful alternative or adjunct therapy for relieving cancer pain.
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Yue
Y
Liu
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Ying
Y
Liang
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Bailing
B
Hou
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Ming
M
Liu
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Xuli
X
Yang
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Chenglong
C
Liu
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Juan
J
Zhang
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Wei
W
Zhang
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China. Electronic address: mazhengliang1964@163.com.
Zhengliang
Z
Ma
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China. Electronic address: xiaopinggu1@gmail.com.
Xiaoping
X
Gu
D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000150:complications*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D007278:Injections, Spinal; D016547:Kinesins / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D010146:Pain / Q000209:etiology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D021381:Protein Transport; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D016547:Kinesins; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; C409642:KIF17 protein, mouse; C121001:NR2B NMDA receptor; C072105:KN 93; D000096926:Benzenesulfonamides
Bone cancer pain; Calcium/calmodulin-dependent protein kinase II; KN93; N-methyl-d-aspartate receptor; N-methyl-d-aspartate receptor 2B subunit