Clioquinol induces autophagy by down-regulation of calreticulin in human neurotypic SH-SY5Y cells

CQ, 5-chloro-7-iodo-8-quinolinol, entered the market as an external antimicrobial agent for skin as early as 1899, and subsequently was sold as an oral drug to treat indigestion and diarrhea by Ciba-Geigy (now Novartis) in the 1930s [1]. In the early 1970s, the outbreak of SMON in Japan was proved to be related to the overdose of CQ [2], because researchers found the patients' tongues would turn blackish green that was an iron deposit of CQ [3]. So Ciba-Geigy withdrew the drug from the global market, thus ending the era of CQ as an over-the-counter drug in March 1985 [4]. In 1990, Ashley I. Bush discovered that CQ had a therapeutic effect on Alzheimer's disease (AD) mice by chelating Zn2+ and Cu2+ in amyloid plaques. This study made CQ as a potential candidate for treating neurodegenerative diseases [5]. A large number of studies have proved that CQ mainly works by affecting Zn2+, Fe2+ and Cu2+ [6]. Furthermore, our previous study showed that CQ could also cause an increase in [Ca2+]i. Further mechanism studies have demonstrated that the increase in [Ca2+]i caused by CQ leads to S-phase cell cycle arrest, while autophagy caused by CQ was independent of [Ca2+]i [7]. Thus, CQ regulates cell cycle and autophagy in different calcium-dependent ways, Autophagy is a signaling pathway that reduces endoplasmic reticulum stress by clearing unfolded/misfolded proteins [8]. This process plays an important role in maintaining function of neurons [9,10]. CRT, a high-capacity calcium-binding molecular chaperone, is a critical component of protein quality control including protein synthesis and folding in the ER [11]. In addition to regulating the UPR effect caused by ER stress and stabilizing [Ca2+]i, the molecular chaperone CRT also plays an important role in the regulation of autophagy and apoptosis [12]. Nasrin Mesaeli et al. found that in CRT-deficient cells, ER stress maintains cell survival by inducing autophagy [13]. Although autophagy is considered to be a mechanism of cell self-protection, excessive up-regulation of autophagy-related genes can also cause cell apoptosis [8]. Narcin Palavan-Unsal et al. found that CRT is a fine-tuning molecule that activates ER stress to cause apoptosis in colon cancer cells treated by epibrassinolide [14]. Since our previous studies have shown that CQ could induce autophagy in human neurotypic SH-SY5Y cells [7], we wondered how CRT regulates ER stress and ultimately affects autophagy in the cells treated by CQ.

The purpose of the present study was to investigate the effect of CQ on the expression of CRT in SH-SY5Y cells, and explore the involvement of CRT in the mode of action of CQ in the neurotypic cells.

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