The CK1ε/SIAH1 axis regulates AXIN1 stability in colorectal cancer cells.

Casein kinase 1ε (CK1ε) and axis inhibitor 1 (AXIN1) are crucial components of the ß-catenin destruction complex in canonical Wnt signaling. CK1ε has been shown to interact with AXIN1, but its physiological function and role in tumorigenesis remain unknown. In this study, we found that CK1δ/ε inhibitors significantly enhanced AXIN1 protein level in colorectal cancer (CRC) cells through targeting CK1ε. Mechanistically, CK1ε promoted AXIN1 degradation by the ubiquitin-proteasome pathway by promoting the interaction of E3 ubiquitin-protein ligase SIAH1 with AXIN1. Genetic or pharmacological inhibition of CK1ε and knockdown of SIAH1 downregulated the expression of Wnt/ß-catenin-dependent genes, suppressed the viability of CRC cells, and restrained tumorigenesis and progression of CRC in vitro and in vivo. In summary, our results demonstrate that CK1ε exerted its oncogenic role in CRC occurrence and progression by regulating the stability of AXIN1. These findings reveal a novel mechanism by which CK1ε regulates the Wnt/ß-catenin signaling pathway and highlight the therapeutic potential of targeting the CK1ε/SIAH1 axis in CRC.

Dexmedetomidine pretreatment attenuates isoflurane-induced neurotoxicity via inhibiting the TLR2/NF-κB signaling pathway in neonatal rats.

Isoflurane is a commonly used inhalational anesthetic that can induce neurotoxicity, while Dexmedetomidine (Dex) has significant neuroprotective effects. In our study, we explored the effects of Dex on isoflurane-induced neurotoxicity through the TLR2/NF-κB signaling pathway. Seven-day old neonatal Sprague-Dawley rats pretreated with 25, 50, 75 µg/kg Dex were exposed to 0.75% isoflurane for 6 h. Spatial learning and memory abilities were detected by Morris water maze test. Ultrastructure of hippocampal neurons, neuronal apoptosis, and the levels of TLR2/NF-κB signaling pathway-related factors were determined. Besides, TLR2 agonist Pam3CSK4 or NF-κB inhibitor BAY11-7082 was injected to further validate the involvement of TLR2/NF-κB signaling following Dex treatment. Consequently, we found isoflurane inhalation resulted in increased cell apoptosis, inflammation and TLR2/NF-κB signaling pathway activation, and decreased PSD95 expression and spatial learning and memory abilities. Dex led to decreased inflammation, improved neuronal structure and viability in rats as well as enhanced spatial learning and memory abilities of rats, and it inactivated the TLR2/NF-κB signaling pathway. Additionally, Pam3CSK4 injection reversed the protective effects of Dex on isoflurane-induced neurotoxicity. In conclusion, this study provided evidence that Dex could alleviate isoflurane-induced neurotoxicity through inhibition of the TLR2/NF-κB signaling pathway. The findings may offer novel insights for the clinical usage of anesthetics.