Human Cancer Biology Protein Kinase C-d–Mediated Recycling of Active KIT in Colon Cancer

Purpose: Abnormal signaling through receptor tyrosine kinase (RTK) moieties is important in tumorigenesis and drug targeting of colorectal cancers. Wild-type KIT (WT-KIT), a RTK that is activated upon bindingwith stemcell factor (SCF), is highly expressed in some colon cancers; however, little is knownabout the functional role of SCF-dependent KIT activation in colon cancer pathogenesis.We aimed to elucidate the conditions and roles of WT-KIT activation in colon cancer tumorigenesis. Experimental Design: Colorectal cancers with KIT expression were characterized by immunoblotting and immunohistochemistry. The biologic alterations after KIT-SCF binding were analyzed with or without protein kinase C (PKC) activation. Results:We found that WT-KIT was expressed in a subset of colon cancer cell lines and was activated by SCF, leading to activation of downstream AKT and extracellular signal-regulated kinase (ERK) signaling pathways.We also showed that KIT expression gradually decreased, after prolonged SCF stimulation, due to lysosomal degradation. Degradation of WT-KIT after SCF binding was significantly rescued when PKC was activated.Wealso showed the involvement of activatedPKC-d in the recyclingofWT-KIT.We further showed that a subset of colorectal cancers exhibit expressions of both WT-KIT and activated PKC-d and that expression of KIT is correlated with poor patient survival (P 1⁄4 0.004). Conclusions:Continuous downstream signal activation after KIT-SCF binding is accomplished through PKC-d–mediated recycling of KIT. This sustained KIT activation may contribute to tumor progression in a subset of colon cancers with KIT expression and might provide the rationale for a therapeutic approach targeting KIT. Clin Cancer Res; 19(18); 1–11. 2013 AACR.