Page 42 - ebook

[B. Cell Biology/Stem Cell] B-21

Casein kinase 1-induced regulation of autophagy and

apoptosis in chloroquine-mediated adult retinal pigment

epithelial-19 cells

Haesung Lee¹, Long Ngo Hoang¹, Ngoc Buu Tran¹, Sook-Jeong Lee¹*

¹Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Jeonbuk National

University, Jeonju, Jeollabuk-do 54896, Korea

The antimalarial drug chloroquine (CQ) is a lysosomotropic agent and is currently used as a potential anticancer

agent as well as an autophagy inhibitor, also induces retinopathy in which characterized by lysosomotropic alteration.
D4476 is a highly effective, selective ATP-competitive casein kinase 1 (CK1) inhibitor, which may prevent or enhance

apoptosis. In this study, we examined whether D4476 could attenuate retinopathy induced by CQ in adult human
retinal pigment epithelial (ARPE-19) cells. CQ-treated ARPE-19 cells resulted in defective lysosomal degradation and

caused accumulation of autophagosomes. Furthermore, the disruption of autophagy initiation and the formation of
autolysosome was caused by Beclin 1 interacting with Bcl-2, which was trapped by CQ. D4476, on the other hand,

mitigated CQ-induced effects, rescuing ARPE-19 cells from CQ-induced toxicity by modulating the association of
Beclin 1 and Bcl-2. As a result, D4476 regulates autophagy and apoptosis simultaneously by upregulating autophagy
flux, decreasing ROS formation, and activating the expression of anti-apoptotic proteins via inhibition of mTOR, JNK,

and p38 MAPK signals. In conclusion, D4476 appears to be a promising treatment strategy for CQ-mediated

retinopathy.