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Protein Kinase C-δ–Mediated Recycling of Active KIT in Colon Cancer

Title
 Protein Kinase C-δ–Mediated Recycling of Active KIT in Colon Cancer
Authors
 Misun Park; Won Kyu Kim; Hoguen Kim; Sung Hee Baek; Hye Jin Nam; Hyunki Kim; Minhee Park; Meiying Song
Issue Date
2013
Journal Title
 Clinical Cancer Research
ISSN
 1078-0432
Citation
 Clinical Cancer Research, Vol.19(18) : 4961~4971, 2013
Abstract
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 binding with stem cell factor (SCF), is highly expressed in some colon cancers; however, little is known about 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. We also showed the involvement of activated PKC-δ in the recycling of WT-KIT. We further showed that a subset of colorectal cancers exhibit expressions of both WT-KIT and activated PKC-δ and that expression of KIT is correlated with poor patient survival (P = 0.004). CONCLUSIONS: Continuous downstream signal activation after KIT-SCF binding is accomplished through PKC-δ-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.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/87602
DOI
10.1158/1078-0432.CCR-13-0131
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Pathology
Yonsei Authors
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Link
 http://clincancerres.aacrjournals.org/content/19/18/4961.long
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