Fig. 6

The combination of CAMKII inhibitor KN93 and gemcitabine exhibited an enhanced anti-tumor activity in ICC. a Representative MRI images and IHC staining of p-CAMKII in patients receiving gemcitabine-based chemotherapy. b CCK8 assay-based detection of inhibitory effect of KN93 and gemcitabine on CCLP1 cells. c Synergy score of the combination of gemcitabine and KN-93 for CCLP1. d, e In vivo detection of the therapeutic effect of KN93 and gemcitabine combined treatment. f The weight of nude mice from CTR, KN93, gemcitabine, KN93 and gemcitabine combined treatment group. g Tunel-based detection of apoptosis in CCLP1 xenograft from different groups. h IHC-based detection of Ki67 in CCLP1 xenograft from different groups. i The abstract figure of the regulatory role of acetylcholine/CHRNA5 axis in ICC: acetylcholine, derived from nerve fibers ending or cancer cells, could activate nAChR to induce the influx of Ca2+, and Ca2+-mediated CAMKII activation further phosphorylate and inactivate GSK3β, increasing the activity of β-catenin in ICC. Enhanced β-catenin activity increased the migration ability and resistance to gemcitabine in ICC. Enhanced β-catenin activity also increased the generation of BDNF to stimulate the axonogenesis, forming an Acetylcholine/CHRNA5-BDNF feedback loop to promote tumor progression in ICC. Representative results from at least three experiments are shown. Data are shown as means ± SD. *p < 0.05; **p < 0.005