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

• Published in: British journal of cancer Vol. 108; no. 2; pp. 409 - 419
• Main Authors: DIXON, K. M, LUI, G. Y. L, KOVACEVIC, Z, ZHANG, D, YAO, M, CHEN, Z, DONG, Q, ASSINDER, S. J, RICHARDSON, D. R
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 05.02.2013
• Subjects: Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation; Epithelial Cells - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; Medical sciences; Molecular Diagnostics; Nephrology. Urinary tract diseases; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Prostate - cytology; Prostate - metabolism; Prostatic Neoplasms - metabolism; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - metabolism; RNA Interference; RNA, Small Interfering; Signal Transduction; Smad2 Protein - metabolism; Thiosemicarbazones - pharmacology; Transforming Growth Factor beta - metabolism; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Smad protein; Carcinoma; Prostate disease; Targeting; Extracellular signal-regulated protein kinase; Transforming growth factor β; PTEN; Iron; NDRG1; iron chelators; Cancerology; Metastasis suppressor gene; PTEN Gene; Urogenital system; Male genital diseases; Tumor suppressor gene; SMAD2; Urinary system disease; Enzyme; Transferases; Akt protein kinase; Mitogen-activated protein kinase; AKT; Malignant tumor; Chelating agent; Prostate cancer; Prostate; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2012.582

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-β (TGF-β) 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. 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. 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. NDRG1 has an important role in mediating the tumour-suppressive effects of Dp44mT in prostate cancer via selective targeting of the PI3K/AKT, TGF-β and ERK pathways.