title: CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation.
abstract: CCN family protein 2 (CCN2), also known as connective tissue growth factor, is a secreting protein that modulates multiple cellular events. We previously demonstrated the metastasis-suppressive effect of CCN2 in lung cancer cells. In this study, we investigate the role of CCN2 in anoikis, a form of programmed cell death that is critical in suppressing cancer metastasis. CCN2 binds to the epidermal growth factor receptor (EGFR) and triggers ubiquitination by inhibiting the formation of the β-pix/Cbl complex, resulting in the degradation of EGFR. Binding of CCN2 to EGFR suppresses the phosphorylation of c-Src and extracellular signal-regulated kinase but increases the expression of death-associated protein kinase, which leads to anoikis. Overall, our findings provide evidence validating the use of CCN2 as an anti-metastatic therapy in lung cancer patients, and prospect a potential therapeutic synergy between CCN2 and the anti-EGFR antibody for the treatment of lung cancer.
authors.affiliation: Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: C-C
authors.initials: CC
authors.lastname: Chang
authors.forename: M-H
authors.initials: MH
authors.lastname: Yang
authors.forename: B-R
authors.initials: BR
authors.lastname: Lin
authors.forename: S-T
authors.initials: ST
authors.lastname: Chen
authors.forename: S-H
authors.initials: SH
authors.lastname: Pan
authors.forename: M
authors.initials: M
authors.lastname: Hsiao
authors.forename: T-C
authors.initials: TC
authors.lastname: Lai
authors.forename: S-K
authors.initials: SK
authors.lastname: Lin
authors.forename: Y-M
authors.initials: YM
authors.lastname: Jeng
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chu
authors.forename: R-H
authors.initials: RH
authors.lastname: Chen
authors.forename: P-C
authors.initials: PC
authors.lastname: Yang
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.forename: M-L
authors.initials: ML
authors.lastname: Kuo
mesh_terms: D000595:Amino Acid Sequence; D023102:Anoikis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D064550:Death-Associated Protein Kinases; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D054875:Ubiquitination; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C576606:ARHGEF7 protein, human; D051017:Apoptosis Regulatory Proteins; D020662:Guanine Nucleotide Exchange Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; D055513:Connective Tissue Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases