Double cortin-like kinase 1(DCLK1)exhibits high expression levels across various cancers,notably in human colorectal cancer(CRC).Diacerein,a clinically approved interleukin(IL)-1βinhibitor for osteoarthritis treatmen...Double cortin-like kinase 1(DCLK1)exhibits high expression levels across various cancers,notably in human colorectal cancer(CRC).Diacerein,a clinically approved interleukin(IL)-1βinhibitor for osteoarthritis treatment,was evaluated for its impact on CRC proliferation and migration,alongside its underlying mechanisms,through both in vitro and in vivo analyses.The study employed MTT assay,colony formation,wound healing,transwell assays,flow cytometry,and Hoechst 33342 staining to assess cell proliferation,migration,and apoptosis.Additionally,proteome microarray assay and western blotting analyses were conducted to elucidate diacerein’s specific mechanism of action.Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo.Through high-throughput proteomics microarray and molecular docking studies,we identified that diacerein directly interacts with DCLK1.Mechanistically,the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed.Furthermore,diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets,including MCL-1,VEGF,and survivin,thereby inhibiting CRC progression in a mouse model,thereby inhibiting CRC progression in a mouse model.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82173856 and 82203322)the Natural Science Foundation of Zhejiang Province(Nos.LY21H300005 and LGF22H030014)+1 种基金Wenzhou Municipal Science and Technology Bureau(Nos.ZY2020025 and H20210009)the Science and Technology Innovation Activity Plan for College Students of Zhejiang Province(No.2019R413012)。
文摘Double cortin-like kinase 1(DCLK1)exhibits high expression levels across various cancers,notably in human colorectal cancer(CRC).Diacerein,a clinically approved interleukin(IL)-1βinhibitor for osteoarthritis treatment,was evaluated for its impact on CRC proliferation and migration,alongside its underlying mechanisms,through both in vitro and in vivo analyses.The study employed MTT assay,colony formation,wound healing,transwell assays,flow cytometry,and Hoechst 33342 staining to assess cell proliferation,migration,and apoptosis.Additionally,proteome microarray assay and western blotting analyses were conducted to elucidate diacerein’s specific mechanism of action.Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo.Through high-throughput proteomics microarray and molecular docking studies,we identified that diacerein directly interacts with DCLK1.Mechanistically,the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed.Furthermore,diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets,including MCL-1,VEGF,and survivin,thereby inhibiting CRC progression in a mouse model,thereby inhibiting CRC progression in a mouse model.
