Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-kappaB signaling pathways.
Notch signaling is involved in a variety of cellular processes, such as cell fate specification, differentiation, proliferation, and survival. Notch-1 over-expression has been reported in prostate cancer metastases. Likewise, Notch ligand Jagged-1 was found to be over-expressed in metastatic prostate cancer compared to localized prostate cancer or benign prostatic tissues, suggesting the biological significance of Notch signaling in prostate cancer progression. However, the mechanistic role of Notch signaling and the consequence of its down-regulation in prostate cancer have not been fully elucidated. Using multiple cellular and molecular approaches such as MTT assay, apoptosis assay, gene transfection, real-time RT-PCR, Western blotting, migration, invasion assay and ELISA, we found that down-regulation of Notch-1 or Jagged-1 was mechanistically associated with inhibition of cell growth, migration, invasion and induction of apoptosis in prostate cancer cells, which was mediated via inactivation of Akt, mTOR, and NF-kappaB signaling. Consistent with these results, we found that the down-regulation of Notch-1 or Jagged-1 led to decreased expression and the activity of NF-kappaB downstream genes such as MMP-9, VEGF, and uPA, contributing to the inhibition of cell migration and invasion. Taken together, we conclude that the down-regulation of Notch-1 or Jagged-1 mediated inhibition of cell growth, migration and invasion, and the induction of apoptosis was in part due to inactivation of Akt, mTOR, and NF-kappaB signaling pathways. Our results further suggest that inactivation of Notch signaling pathways by innovative strategies could be a potential targeted approach for the treatment of metastatic prostate cancer.
Wang
Zhiwei
Z
Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA. zhiweiwang@med.wayne.edu
Li
Yiwei
Y
Banerjee
Sanjeev
S
Kong
Dejuan
D
Ahmad
Aamir
A
Nogueira
Veronique
V
Hay
Nissim
N
Sarkar
Fazlul H
FH
D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D016328:NF-kappa B; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases