Decorin antagonizes Met receptor activity and down-regulates {beta}-catenin and Myc levels.
A theme emerging during the past few years is that members of the small leucine-rich proteoglycan gene family affect cell growth by interacting with multiple receptor tyrosine kinases (RTKs), mostly by a physical down-regulation of the receptors, thereby depriving tumor cells of pro-survival signals. Decorin binds and down-regulates several RTKs, including Met, the receptor for hepatocyte growth factor. Here we demonstrate that decorin blocks several biological activities mediated by the Met signaling axis, including cell scatter, evasion, and migration. These effects were mediated by a profound down-regulation of noncanonical β-catenin levels. In addition, Myc, a downstream target of β-catenin, was markedly down-regulated by decorin, whereas phosphorylation of Myc at threonine 58 was markedly induced. The latter is known to destabilize Myc and target it for proteasomal degradation. We also discovered that systemic delivery of decorin using three distinct tumor xenograft models caused down-regulation of Met and a concurrent suppression of β-catenin and Myc levels. We found that decorin protein core labeled with the near infrared dye IR800 specifically targeted the tumor cells expressing Met. Even 68-h post-injection, decorin was found to reside within the tumor xenografts with little or no binding to other tissues. Collectively, our results indicate a role for a secreted proteoglycan in suppressing the expression of key oncogenic factors required for tumor progression.
Department of Pathology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Simone
S
Buraschi
Nutan
N
Pal
Nadia
N
Tyler-Rubinstein
Rick T
RT
Owens
Thomas
T
Neill
Renato V
RV
Iozzo
D017738:Alkanesulfonic Acids / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D058575:Decorin / Q000737:chemistry* / Q000378:metabolism; D018450:Disease Progression; D004285:Dogs; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D017738:Alkanesulfonic Acids; D058575:Decorin; C000607808:IRDye 800CW NHS ester; D007211:Indoles; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; D019859:Proto-Oncogene Proteins c-met; D046988:Proteasome Endopeptidase Complex