Fig. 7
Treatment with soluble form of disintegrator of KITENIN complex, DKC-C14S the suppresses the tumor growth. A Pharmacokinetic parameters of DKC-C14S. AUCt: area under the curve from zero time to last sampling time; Cmax: maximum concentration; Tmax: time to reach Cmax; F: bioavailability; CL: total body clearance; t1/2: half-life; Vss: volume of distribution at steady state (1median (range) and 2F value was calculated as following equation; F(%) = 100xAUCt_oral/AUCt_iv). All data expressed as mean ± standard deviation. B Treatment of DKC-C14S significantly reduces the tumor formation in a tumor model with higher expression levels of KITENIN. 1 × 106 CT-26/KITENIN-V5 cells were inoculated subcutaneously into BALB/c mice. After the tumors grew for 1 week, the DKC-C14S was given intravenously every other day for 14 days. C–F Mice were sacrificed on day 30 and images of tumors, tumors sizes, tumor weights and body weight in different treatment groups were acquired (mean ± SD). G–H Fluorescence area of images obtained from a fluorescence-labeled organism bioimaging instrument (FOBI) system (mean ± SD, n = 8). An asterisk indicates a significant difference between indicated groups. * p < 0.05; ** p < 0.01; *** p < 0.001, NS, no significant difference between groups. The decreased levels of KITENIN, ERK, metabolic marker and transcriptional regulators in tumor tissues given DKC-C14S. I KITENIN and its downstream signals protein ERK (total ERK and p-ERK) protein levels were investigated from the tumors tissues. J The protein levels of GLUT1, HK2, PKM1, PKM2, c-Myc, hnRNPA1, HIF-1α, β-catenin, and Cyclin D1 were examined via immunoblot analyses tumors collected from both groups, vehicle and DKC-C14S (5 mpk). K Schematic showing how the oncoprotein KITENIN affects metabolic and non-metabolic pathways regulating aerobic glycolysis. Overexpression of KITENIN upregulates the expression of the AP-1 and TCF4 target genes. Here, overexpression of c-Myc upregulates hnRNPI, hnRNPA1 and hnRNPA2 expressions, which are responsible for the PKM2/PKM1 ratio, and increases the PKM2/PKM1 ratio. All nuclear activities that occur with KITENIN overexpression upregulate the level of proteins responsible for aerobic glycolysis. Overexpressed in the cytoplasm PKM2, undergoes nuclear translocation, where it forms a complex with β-catenin and HIF-1a, feeding a positive feedback mechanism. The disintegration of the KITENIN complex by DKC compounds and the knockdowns inhibit KITENIN-mediated nuclear activity and upregulation of aerobic glycolysis