Integrin‐linked kinase regulates E‐cadherin expression through PARP‐1

McPhee, Timothy R.; McDonald, Paul C.; Oloumi, Arusha; Dedhar, Shoukat

doi:10.1002/dvdy.21685

Cited by 71 publications

(65 citation statements)

References 59 publications

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“…Likewise, PARP-1 was identified as a SIRE-binding protein. ILK silencing inhibited PARP-1 binding to SIRE, and PARP-1 silencing decreased both Zeb1 and Snail, which resulted in the upregulation of E-cadherin (35). Vimentin, the intermediate filament protein, is an important marker of the EMT and a requisite regulator of mesenchymal cell migration (36).…”

Section: Discussionmentioning

confidence: 99%

Targeting Integrin-Linked Kinase Suppresses Invasion and Metastasis through Downregulation of Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma

Han

Raven

et al. 2015

Molecular Cancer Therapeutics

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Renal cell carcinoma (RCC) is the most common malignancy in the kidney. Antiangiogenic targeted therapies inhibit the progression of RCC, but have limited impacts on invasion or metastasis of tumor cells. Integrin-linked kinase (ILK) is a serine/threonine kinase implicated in the regulation of cell growth/survival, cellcycle progression, epithelial-mesenchymal transition (EMT), invasion/migration, and angiogenesis. However, the role of ILK in RCC has not been evaluated. We investigated the role of ILK on cancer progression and metastasis and the therapeutic potential of ILK inhibition in RCC. Our investigation reveals that ILK is expressed at a low level in normal cells and low-stage RCC cells and is highly expressed in advanced and metastatic cells. Caki-1, a metastatic RCC cell line, showed higher expression of molecular EMT markers, including Snail and Zeb1, but decreased activity of GSK3b. Knockdown of ILK using small interference (si)-ILK minimally inhibited tumor proliferation and cell-cycle progression was not significantly affected. However, ILK knockdown suppressed the formation of stress fibers and focal adhesions and impeded phenotypic EMT markers, including cell migration and invasion, in Caki-1 and UMRC-3 cells. Finally, in vivo knockdown of ILK suppressed the progression, invasion, and metastasis of primary RCC in nude mice by downregulation of EMT markers (Snail, Zeb1, vimentin,. Our results show that ILK may be essential for invasion and metastasis in RCC and regulates vimentin and E-cadherin expression by regulating the EMT-related transcription factors Snail and Zeb1. These results suggest that ILK may be a potential target in RCC.

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Section: Discussionmentioning

confidence: 99%

Targeting Integrin-Linked Kinase Suppresses Invasion and Metastasis through Downregulation of Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma

Han

Raven

et al. 2015

Molecular Cancer Therapeutics

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“…Previously it has been reported that ILK-dependent activation of Snail1 transcription required PARP-1 binding to ILK promoter (McPhee et al, 2008). To analyze the involvement of ILK in the interaction between PARP-1 and Snail1, ILK was knocked down using siRNA (Figure 4h).…”

Section: Snail1 Protein Is Polyadp-ribosylatedmentioning

confidence: 99%

“…Recently it has been demonstrated that poly(ADP-ribose) polymerase-1 (PARP-1) is involved in the activation of Snail1 gene transcription through binding to the integrin-linked kinase (ILK) promoter (McPhee et al, 2008). PARP-1 is the principal member of a family of enzymes with poly(ADP-ribosyl)ation catalytic capacity.…”

Section: Introductionmentioning

confidence: 99%

Poly(ADP-ribose)-dependent regulation of Snail1 protein stability

et al. 2011

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Snail1 is a master regulator of the epithelial-mesenchymal transition (EMT) and has been implicated in key tumor biological processes such as invasion and metastasis. It has been previously shown that poly(ADP-ribose) polymerase-1 (PARP-1) knockdown, but not PARP inhibition, downregulates the expression of Snail1. In this study we have characterized a novel regulatory mechanism controlling Snail1 protein expression through poly(ADP-ribosyl)ation. The effect is not only limited to repression of Snail1 transcription but also to downregulated Snail1 protein stability. PARP-1 (but not PARP-2) poly(ADP) ribosylates Snail1, both in vivo and in vitro, and interacts with Snail1, an association that is sensitive to PARP inhibitors. PARP inhibition has also clear effects on EMT phenotype of different tumor cells, including Snail1 downregulation, E-cadherin upregulation, decreased cell elongation and invasiveness. Therefore, this study reveals a new regulatory mechanism of Snail1 activation through poly(ADP-ribosyl)ation with consequences in malignant transformation through EMT.

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“…Given that both Cten and integrinlinked kinase (ILK) seem to regulate cell motility and downregulate E-cadherin (Somasiri et al, 2001;Oloumi et al, 2004;McPhee et al, 2008), we hypothesised that Cten may signal through ILK. In addition, we evaluated the prognostic significance of Cten in a series of CRC and we used an in vivo model to test whether Cten could influence tumour metastasis.…”

Section: Introductionmentioning

confidence: 99%

Cten signals through integrin-linked kinase (ILK) and may promote metastasis in colorectal cancer

et al. 2011

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CTEN/TNS4 is an oncogene in colorectal cancer (CRC), which can induce cell motility although its mechanistic basis of activity and the clinical implications of Cten expression are unknown. As Cten is in complex with integrins at focal adhesions, we hypothesised that it may interact with integrin-linked kinase (ILK). Through forced expression and knockdown of Cten in HCT116 and SW620 (respectively, showing low and high Cten expression), we showed that Cten could regulate ILK. However, inhibition of ILK after forced expression of Cten abrogated the motility-inducing effects of Cten, thereby demonstrating that the Cten-ILK interaction was functionally relevant. Combined knockdown of Cten and ILK had no additive effects on cell motility compared with knockdown of each individually. In order to investigate the clinical implications of Cten expression, a series of 462 CRCs were evaluated by immunohistochemistry. High expression of Cten was associated with advanced Dukes' stage (Po0.001), poor prognosis (Po0.001) and distant metastasis (P ¼ 0.008). The role of Cten in metastasis was tested by (a) intrasplenic injection of CRC cells stably transfected with a Cten expression vector into nude mice and (b) testing a series of primary human CRCs and their metastases by immunohistochemistry. Compared with controls, mice injected with cells expressing Cten developed larger tumours in the spleen (Po0.05) and liver (Po0.05). In the human cases, compared with primary tumours, the metastatic deposits had a significantly higher frequency of nuclear localisation of Cten (P ¼ 0.002). We conclude that Cten expression is of prognostic significance in CRC, and we delineate a Cten-ILK pathway controlling cell motility and possibly promoting metastasis. Oncogene (2011Oncogene ( ) 30, 2997 doi:10.1038/onc.2011 published online 21 February 2011 Keywords: Cten; integrin-linked kinase; metastasis Introduction C-terminal tensin-like (Cten, TNS4) is a member of the Tensin gene family. This gene family comprises four members (TNS1, TNS2, TNS3 and TNS4/Cten) and their products are localised to the cytoplasmic tails of integrins at focal adhesions. Tensins have an important role in various biological processes such as cell adhesion, migration, proliferation, differentiation, apoptosis and invasion (Lo et al., 1994;Chen et al., 2000;Lo, 2004). Human TNS1, TNS2 and TNS3 are highly homologous at their N-and C-termini, but TNS4/ COOH-terminus tensin-like molecule (Cten) is a smaller protein, which shows C-terminus homology but does not contain the N-terminus actin-binding domain that is present in the other tensin proteins (Lo and Lo, 2002). Tensin family proteins interact with several structural and signalling molecules such as vinculin, paxillin, Src, focal adhesion kinase, phosphatidylinositol-3-kinase and Crk-associated substrate p130 CAS , actin as well as integrins. As Cten is a recently described gene, data about its downstream targets are sparse, although recent studies suggest that Cten signalling occurs through the Stat3 pathway (Barbie...

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Integrin‐linked kinase regulates E‐cadherin expression through PARP‐1

Abstract: Repression of E-cadherin expression by the transcription factor, Snail, is implicated in epithelial to mesenchymal transition and cancer progression. We show here that Integrin-Linked Kinase (

Cited by 71 publications

References 59 publications

Targeting Integrin-Linked Kinase Suppresses Invasion and Metastasis through Downregulation of Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma

Targeting Integrin-Linked Kinase Suppresses Invasion and Metastasis through Downregulation of Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma

Poly(ADP-ribose)-dependent regulation of Snail1 protein stability

Cten signals through integrin-linked kinase (ILK) and may promote metastasis in colorectal cancer

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