N‐myc downstream regulated gene 1 modulates Wnt‐β‐catenin signalling and pleiotropically suppresses metastasis

Li, Wen; Xing, Fei; Iiizumi‐Gairani, Megumi; Okuda, Hiroshi; Watabe, Misako; Pai, Sudha K.; Pandey, Puspa R.; Hirota, Shigeru; Kobayashi, Aya; Mo, Yin‐Yuan; Fukuda, Koji; Li, Yang; Watabe, Kounosuke

doi:10.1002/emmm.201100190

Cited by 182 publications

(258 citation statements)

References 57 publications

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“…It has been reported that the combination of Wnt ligands, LRP6 and ATF3 had a significant inverse correlation with metastasis-free survival of prostate cancer patients 34 . Liu et al…”

Section: Discussionmentioning

confidence: 97%

LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis

Ren

Chen

et al. 2015

Nat Commun

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How Wnt signalling including canonical and non-canonical pathways are initiated at the cell surface is not completely understood. Here we report that Wnt receptor Frizzled (Frz) and the co-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. Importantly, through direct binding to Frz, LRP5/6 are able to prevent Frz-regulated non-canonical pathway activation and further non-canonical pathway-mediated tumour metastasis. Knockdown of endogenous LRP5/6 promotes otherwise-nonaggressive tumour cells to migrate in vitro, whereas a soluble recombinant protein of LRP6 ectodomain suppresses migration and metastasis of otherwise-aggressive tumour cells in vitro and in vivo. Furthermore, the expression level of membrane LRP5/6 correlates inversely with metastasis in mouse and human breast cancer. Our study suggests a previously unrecognized mode of receptor interaction, revealing the mechanism of LRP5/6 in inhibition of non-canonical pathway, and a possible clinical use of the LRP6 ectodomain to impede metastasis.

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“…It has been reported that the combination of Wnt ligands, LRP6 and ATF3 had a significant inverse correlation with metastasis-free survival of prostate cancer patients 34 . Liu et al…”

Section: Discussionmentioning

confidence: 97%

LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis

Ren

Chen

et al. 2015

Nat Commun

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“…This was important to establish, as EGFR is a key regulator of numerous oncogenic downstream signaling pathways (31,43) that were previously found to be inhibited by NDRG1 (4,6,8,(17)(18)(19). Considering the differences between tumors regarding their genetic background, all studies were conducted with both cell lines, to gain insight into NDRG1 function and gauge common functions between cell types.…”

Section: Ndrg1 Down-regulates the Expression Of Egfr In Panc-1mentioning

confidence: 99%

“…In fact, we and others recently demonstrated that NDRG1 can be markedly up-regulated by a novel class of anti-cancer agents, namely the di-2-pyridylketone class of thiosemicarbazones, such as di-2-pyri-dylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) 8 and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC; Fig. 1A) (1,3,18,(21)(22)(23).…”

mentioning

confidence: 98%

“…Moreover, these thiosemicarbazones possessed potent and selective anti-cancer activity against a range of tumors both in vitro and in vivo (1,3,(21)(22)(23)25). The potential of these novel compounds is underscored by their marked ability to inhibit tumor cell metastasis in vivo (18) and overcome cancer cell multidrug resistance mediated by P-glycoprotein in vitro and in vivo (23,26). Interestingly, the anti-metastatic effects of these agents were demonstrated to be dependent on their ability to up-regulate NDRG1 in vitro and in vivo (4,18,20), further establishing this metastasis suppressor as an important molecular target for the treatment of cancer.…”

mentioning

confidence: 99%

“…The pathways targeted by the ErbB receptors are dictated by the dimer partners, as each member of this receptor family has distinct biochemical properties and binding partners (27,28). Some of the downstream pathways affected by the EGFR, HER2, and HER3 receptors include the PI3K, RAS, MAPK, WNT, TGF-␤, NF-B, and c-Src pathways (28,35), many of which have been previously shown to be modulated by NDRG1 expression (2,6,8,11,14,(17)(18)(19). Hence, we hypothesized that NDRG1 may potentially affect a wide array of pathways by targeting the ErbB family members.…”

mentioning

confidence: 99%

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The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

Kovačević

Menezes

Sahni

et al. 2016

Journal of Biological Chemistry

113

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N-MYC downstream-regulated gene-1 (NDRG1) is a potent growth and metastasis suppressor that acts through its inhibitory effects on a wide variety of cellular signaling pathways, including the TGF-␤ pathway, protein kinase B (AKT)/PI3K pathway, RAS, etc. To investigate the hypothesis that its multiple effects could be regulated by a common upstream effector, the role of NDRG1 on the epidermal growth factor receptor (EGFR) and other members of the ErbB family, namely human epidermal growth factor receptor 2 (HER2) and human epidermal growth factor receptor 3 (HER3), was examined. We demonstrate that NDRG1 markedly decreased the expression and activation of EGFR, HER2, and HER3 in response to the epidermal growth factor (EGF) ligand, while also inhibiting formation of the EGFR/HER2 and HER2/HER3 heterodimers. In addition, NDRG1 also decreased activation of the downstream MAPKK in response to EGF. Moreover, novel anti-tumor agents of the di-2-pyridylketone class of thiosemicarbazones, namely di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone, which markedly up-regulate NDRG1, were found to inhibit EGFR, HER2, and HER3 expression and phosphorylation in cancer cells. However, the mechanism involved appeared dependent on NDRG1 for di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone, but was independent of this metastasis suppressor for di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone. This observation demonstrates that small structural changes in thiosemicarbazones result in marked alterations in molecular targeting. Collectively, these results reveal a mechanism for the extensive downstream effects on cellular signaling attributed to NDRG1. Furthermore, this study identifies a novel approach for the treatment of tumors resistant to traditional EGFR inhibitors.

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The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion

et al. 2017

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Experimental and clinical evidence suggests that N‐myc downregulated gene 1 (NDRG1) functions as a suppressor of prostate cancer metastasis. Elucidating pathways that drive survival and invasiveness of NDRG1‐deficient prostate cancer cells can help in designing therapeutics to target metastatic prostate cancer cells. However, the molecular mechanisms that lead NDRG1‐deficient prostate cancer cells to increased invasiveness remain largely unknown. In this study, we demonstrate that NDRG1‐deficient prostate tumors have decreased integrin expression and reduced cell adhesion and motility. Our data indicate that loss of NDRG1 differentially affects Rho GTPases. Specifically, there is a downregulation of active RhoA and Rac1 GTPases with a concomitant upregulation of active Cdc42 in NDRG1‐deficient cells. Live cell imaging using a fluorescent sensor that binds to polymerized actin revealed that NDRG1‐deficient cells have restricted actin dynamics, thereby affecting cell migration. These cellular and molecular characteristics are in sharp contrast to what is expected after loss of a metastasis suppressor. We further demonstrate that NDRG1‐deficient cells have increased resistance to anoikis and increased invasiveness which is independent of its elevated Cdc42 activity. Furthermore, NDRG1 regulates expression and glycosylation of EMMPRIN, a master regulator of matrix metalloproteases. NDRG1 deficiency leads to an increase in EMMPRIN expression with a concomitant increase in matrix metalloproteases and thus invadopodial activity. Using a three‐dimensional invasion assay and an in vivo metastasis assay for human prostate xenografts, we demonstrate that NDRG1‐deficient prostate cancer cells exhibit a collective invasion phenotype and are highly invasive. Thus, our findings provide novel insights suggesting that loss of NDRG1 leads to a decrease in actin‐mediated cellular motility but an increase in cellular invasion, resulting in increased tumor dissemination which positively impacts metastatic outcome.

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N‐myc downstream regulated gene 1 modulates Wnt‐β‐catenin signalling and pleiotropically suppresses metastasis

Cited by 182 publications

References 57 publications

LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis

LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

The prostate metastasis suppressor gene NDRG1 differentially regulates cell motility and invasion

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