Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells.
Although many studies have been done to uncover the mechanisms by which down-regulation of Notch-1 exerts its anti-tumor activity against a variety of human malignancies, the precise molecular mechanisms remain unclear. In the present study, we investigated the cellular consequence of Notch-1 down-regulation and also assessed the molecular consequence of Notch-1-mediated alterations of its downstream targets on cell viability and apoptosis in prostate cancer (PCa) cells. We found that the down-regulation of Notch-1 led to the inhibition of cell growth and induction of apoptosis, which was mechanistically linked with down-regulation of Akt and FoxM1, suggesting for the first time that Akt and FoxM1 are downstream targets of Notch-1 signaling. Moreover, we found that a "natural agent" (genistein) originally discovered from soybean could cause significant reduction in cell viability and induced apoptosis of PCa cells, which was consistent with down-regulation of Notch-1, Akt, and FoxM1. These results suggest that down-regulation of Notch-1 by novel agents could become a newer approach for the prevention of tumor progression and/or treatment, which is likely to be mediated via inactivation of Akt and FoxM1 signaling pathways in PCa.
Wang
Zhiwei
Z
Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA. zhiweiwang@med.wayne.edu
Li
Yiwei
Y
Ahmad
Aamir
A
Banerjee
Sanjeev
S
Azmi
Asfar S
AS
Kong
Dejuan
D
Wojewoda
Christine
C
Miele
Lucio
L
Sarkar
Fazlul H
FH
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D051057:Proto-Oncogene Proteins c-akt