Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression.
Notch is a highly conserved transmembrane receptor that determines cell fate. Notch signaling denotes cleavage of the Notch intracellular domain, its translocation to the nucleus, and subsequent activation of target gene transcription. Involvement of Notch signaling in several cancers is well known, but its role in melanoma remains poorly characterized. Here we show that the Notch1 pathway is activated in human melanoma. Blocking Notch signaling suppressed whereas constitutive activation of the Notch1 pathway enhanced primary melanoma cell growth both in vitro and in vivo yet had little effect on metastatic melanoma cells. Activation of Notch1 signaling enabled primary melanoma cells to gain metastatic capability. Furthermore, the oncogenic effect of Notch1 on primary melanoma cells was mediated by beta-catenin, which was upregulated following Notch1 activation. Inhibiting beta-catenin expression reversed Notch1-enhanced tumor growth and metastasis. Our data therefore suggest a beta-catenin-dependent, stage-specific role for Notch1 signaling in promoting the progression of primary melanoma.
Balint
Klara
K
The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Xiao
Min
M
Pinnix
Chelsea C
CC
Soma
Akinobu
A
Veres
Imre
I
Juhasz
Istvan
I
Brown
Eric J
EJ
Capobianco
Anthony J
AJ
Herlyn
Meenhard
M
Liu
Zhao-Jun
ZJ
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D018450:Disease Progression; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D016513:Mice, SCID; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014280:Triglycerides / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D006131:Growth Inhibitors; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D014280:Triglycerides; D051176:beta Catenin; D005680:gamma-Aminobutyric Acid; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol