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Cell Growth, Migration and Invasion, and Induces Apoptosis Via Inactivation of Akt, mTOR, and NF-κB Signaling Pathways (Retracted article. See vol. 117, pg. 1960, 2016)
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Cell Growth, Migration and Invasion, and Induces Apoptosis Via Inactivation of Akt, mTOR, and NF-κB Signaling Pathways (Retracted article. See vol. 117, pg. 1960, 2016)
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DOI：
10.1002/jcb.22451
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发表时间：
2010-03-01
影响因子：
4
通讯作者：
Sarkar, Fazlul H.
中科院分区：
文献类型：
--
作者：
Wang, Zhiwei;Li, Yiwei;Sarkar, Fazlul H.
Notch信号参与多种细胞过程，如细胞命运规范、分化、增殖和存活。Notch-1过表达在前列腺癌转移中有报道。同样，Notch配体Jagged-1在转移性前列腺癌中比局限性前列腺癌或良性前列腺组织中过表达，提示Notch信号在前列腺癌进展中的生物学意义。然而，Notch信号的机制作用及其下调在前列腺癌中的作用尚未完全阐明。通过MTT实验、凋亡实验、基因转染、实时RT-PCR、Western blotting、迁移、侵袭实验和ELISA等多种细胞和分子方法，我们发现Notch-1或Jagged-1的下调与抑制前列腺癌细胞生长、迁移、侵袭和诱导凋亡的机制相关，其机制是通过Akt、mTOR和NF-kappa B信号的失活介导的。与这些结果一致，我们发现Notch-1或Jagged-1的下调导致NF-kappa B下游基因如MMP-9、VEGF、uPA的表达和活性降低，从而抑制细胞迁移和侵袭。综上所述，我们得出结论，Notch-1或Jagged-1的下调介导了细胞生长、迁移和侵袭的抑制以及细胞凋亡的诱导，部分原因是Akt、mTOR和NF-kappa B信号通路失活。我们的研究结果进一步表明，通过创新策略使Notch信号通路失活可能是治疗转移性前列腺癌的潜在靶向方法。j .细胞。中国生物医学工程学报，2009,31(2):526 - 536。(C) 2010 Wiley-Liss。公司。
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 prostate 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-kappa B 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-kappa B 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-kappa B 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. J. Cell. Biochem. 109: 726-736, 2010. (C) 2010 Wiley-Liss. Inc.