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

Authors
 Misun Park  ;  Won Kyu Kim  ;  Meiying Song  ;  Minhee Park  ;  Hyunki Kim  ;  Hye Jin Nam  ;  Sung Hee Baek  ;  Hoguen Kim 
Citation
 CLINICAL CANCER RESEARCH, Vol.19(18) : 4961-4971, 2013 
Journal Title
CLINICAL CANCER RESEARCH
ISSN
 1078-0432 
Issue Date
2013
MeSH
Apoptosis ; Blotting, Western ; Cell Adhesion ; Cell Movement* ; Cell Proliferation* ; Colorectal Neoplasms/metabolism* ; Colorectal Neoplasms/mortality ; Colorectal Neoplasms/pathology* ; Disease Progression ; Extracellular Signal-Regulated MAP Kinases/genetics ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fluorescent Antibody Technique ; Humans ; Immunoenzyme Techniques ; Immunoprecipitation ; Lysosomes/metabolism ; Neoplasm Staging ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Prognosis ; Protein Kinase C-delta/genetics ; Protein Kinase C-delta/metabolism* ; Proto-Oncogene Proteins c-kit/genetics ; Proto-Oncogene Proteins c-kit/metabolism* ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Stem Cell Factor/genetics ; Stem Cell Factor/metabolism ; Survival Rate ; Tissue Array Analysis ; Tumor Cells, Cultured
Keywords
Apoptosis ; Blotting, Western ; Cell Adhesion ; Cell Movement* ; Cell Proliferation* ; Colorectal Neoplasms/metabolism* ; Colorectal Neoplasms/mortality ; Colorectal Neoplasms/pathology* ; Disease Progression ; Extracellular Signal-Regulated MAP Kinases/genetics ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fluorescent Antibody Technique ; Humans ; Immunoenzyme Techniques ; Immunoprecipitation ; Lysosomes/metabolism ; Neoplasm Staging ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Prognosis ; Protein Kinase C-delta/genetics ; Protein Kinase C-delta/metabolism* ; Proto-Oncogene Proteins c-kit/genetics ; Proto-Oncogene Proteins c-kit/metabolism* ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Stem Cell Factor/genetics ; Stem Cell Factor/metabolism ; Survival Rate ; Tissue Array Analysis ; Tumor Cells, Cultured
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.
Full Text
http://clincancerres.aacrjournals.org/content/19/18/4961.long
DOI
10.1158/1078-0432.CCR-13-0131
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Won Kyu(김원규)
Kim, Hyunki(김현기) ORCID logo https://orcid.org/0000-0003-2292-5584
Kim, Hogeun(김호근)
Park, Mi Sun(박미선)
Park, Min Hee(박민희)
Song, Mei Ying(송미영)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/87602
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