Dp44mT targets the AKT, TGF-β and ERK pathways via the metastasis suppressor NDRG1 in normal prostate epithelial cells and prostate cancer cells

被引：97

作者：

Dixon, K. M. ^{[1
,2
]}

Lui, G. Y. L. ^{[1
,2
]}

Kovacevic, Z. ^{[1
,2
]}

Zhang, D. ^{[1
,2
]}

Yao, M. ^{[2
,3
]}

Chen, Z. ^{[1
,2
,4
]}

Dong, Q. ^{[2
,3
,5
]}

Assinder, S. J. ^{[2
,6
]}

Richardson, D. R. ^{[1
,2
]}

机构：

[1] Univ Sydney, Dept Pathol, Sch Med Sci, Sydney Med Sch, Sydney, NSW 2006, Australia

[2] Univ Sydney, Bosch Inst, Sch Med Sci, Prostate Canc Focus Grp,Sydney Med Sch, Sydney, NSW 2006, Australia

[3] Univ Sydney, Dept Endocrinol, Sch Med Sci, Sydney Med Sch, Sydney, NSW 2006, Australia

[4] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Gen Surg Dept, Shanghai 200025, Peoples R China

[5] Univ Western Sydney, Sch Sci & Hlth, Penrith, NSW 2751, Australia

[6] Univ Sydney, Dept Physiol, Sch Med Sci, Sydney Med Sch, Sydney, NSW 2006, Australia

来源：

BRITISH JOURNAL OF CANCER | 2013年 / 108卷 / 02期

基金：

英国医学研究理事会;

关键词：

prostate cancer; iron chelators; NDRG1; PTEN; AKT; SMAD2; SELECTIVE ANTITUMOR-ACTIVITY; IRON CHELATORS; REGULATED GENE-1; TUMOR-METASTASIS; UP-REGULATION; EXPRESSION; GROWTH; PTEN; DRG-1; APOPTOSIS;

D O I：

10.1038/bjc.2012.582

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Effective treatment of prostate cancer should be based on targeting interactions between tumour cell signalling pathways and key converging downstream effectors. Here, we determined how the tumourigenic phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), tumour-suppressive phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and transforming growth factor-beta (TGF-beta) pathways are integrated via the metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1). Moreover, we assessed how the novel anti-tumour agent, Dp44mT, may target these integrated pathways by increasing NDRG1 expression. Methods: Protein expression in Dp44mT-treated normal human prostate epithelial cells and prostate cancer cells (PC-3, DU145) was assessed by western blotting. The role of NDRG1 was examined by transfection using an NDRG1 overexpression vector or shRNA. Results: Dp44mT increased levels of tumour-suppressive PTEN, and decreased phosphorylation of ERK1/2 and SMAD2L, which are regulated by oncogenic Ras/MAPK signalling. Importantly, the effects of Dp44mT on NDRG1 and p-SMAD2L expression were more marked in prostate cancer cells than normal prostate epithelial cells. This may partly explain the anti-tumour selectivity of these agents. Silencing NDRG1 expression increased phosphorylation of tumourigenic AKT, ERK1/2 and SMAD2L and decreased PTEN levels, whereas NDRG1 overexpression induced the opposite effect. Furthermore, NDRG1 silencing significantly reduced the ability of Dp44mT to suppress p-SMAD2L and p-ERK1/2 levels. Conclusion: NDRG1 has an important role in mediating the tumour-suppressive effects of Dp44mT in prostate cancer via selective targeting of the PI3K/AKT, TGF-beta and ERK pathways.

引用

页码：409 / 419

页数：11

共 49 条

[1] Hypoxia induces the activation of the phosphatidylinositol 3-kinase/Akt cell survival pathway in PC12 cells -: Protective role in apoptosis [J].