Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis

Marotta, A.; Tan, Clara; Gray, Virginia; Malik, Sanjeev; Gallinger, S; Sanghera, Jasbinder S.; Dupuis, Beverely; Owen, David A.; Dedhar, Shoukat; Salh, Baljinder

doi:10.1038/sj.onc.1204791

Cited by 73 publications

(52 citation statements)

References 39 publications

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“…Consistent with these transformation models, elevated ILK protein and activity levels are seen in Ewing's Sarcoma (Chung et al, 1998), and in precancerous colonic polyps (Marotta et al, 2001). Elevated ILK expression and activity shows a strong positive correlation with prostate tumor grade (Graff et al, 2001), is associated with metastatic gastric carcinoma (Ito et al, 2003) and correlates with poor patient outcome in malignant melanoma (Dai et al, 2003), altogether suggesting that ILK dysregulation contributes to early and late stages of tumor development.…”

Section: Introductionmentioning

confidence: 51%

ILKAP regulates ILK signaling and inhibits anchorage-independent growth

et al. 2004

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ILKAP is a protein phosphatase 2C that selectively associates with integrin linked kinase, ILK, to modulate cell adhesion and growth factor signaling. We investigated the role of endogenous cellular ILKAP in antagonizing ILK signaling of two key targets, PKB and GSK3b. Silencing of endogenous ILKAP by short interfering RNA (siRNA) stimulated GSK3b phosphorylation at S9, with no effect on PKB S473 phosphorylation. In LNCaP prostate carcinoma cells, transient or stable expression of ILKAP suppressed ILK immune complex kinase activity, demonstrating an interaction between ILKAP and ILK. Consistent with the silencing data, ILKAP inhibition of ILK selectively inhibited S9 phosphorylation of GSK3b without affecting S473 phosphorylation of PKB. The ILKAP-mediated inhibition of S9 phosphorylation was rescued by overexpression of ILK, but not by a dominantnegative ILK mutant. The expression level of cyclin D1, a target of ILK-GSK3b signaling, was inversely correlated with ILKAP protein levels, suggesting that antagonism of ILK modulates cell cycle progression. ILKAP expression increased the proportion of LNCaP cells in G1, relative to vector control cells, and siRNA suppression of ILKAP increased entry of cells into the S phase, consistent with ILK antagonism. Anchorage-independent growth of LNCaP cells was inhibited by ILKAP, suggesting a critical role in the suppression of cellular transformation. Taken together, our results indicate that endogenous ILKAP activity inhibits the ILK-GSK3b signaling axis, and suggest that ILKAP activity plays an important role in inhibiting oncogenic transformation.

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Section: Introductionmentioning

confidence: 51%

ILKAP regulates ILK signaling and inhibits anchorage-independent growth

et al. 2004

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“…Additionally, we demonstrate that both aspirin and sulindac inhibit PKB biochemical activity in an immune complex kinase assay. Based on our previous findings, which indicated that ILK activity is modulated by these agents, we believe that this effect on Ser473 phosphorylation could be mediated through ILK itself (20). However, one cannot rule out that this is a direct effect based upon the inhibitory effects of sulindac on in vitro PKB activity.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrated that sulindac could inhibit the serum-induced activation of ILK. ILK is a putative PDK2 that has been reported to phosphorylate PKB on Ser473; phosphorylation at this critical serine residue in addition to Thr308 phosphorylation results in the activation of the latter (20). Based upon our earlier observations, we postulated that these agents might influence the biochemical activity of PKB in an ILK-dependent fashion.…”

Section: Effects Of Nsaids On Biochemical Activity Of Pkbmentioning

confidence: 96%

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Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide

Marotta

Parhar²,

Hundal³

et al. 2006

Int J Oncol

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Abstract. Non-steroidal anti-inflammatory drugs such as sulindac inhibit human colorectal carcinogenesis through a mechanism involving the direct inhibition of cyclooxygenase (Cox)-2. However, a wealth of recent evidence indicates that these agents might elicit their effects through mechanisms independently of Cox-2. In this study, we investigated the effects of sulindac and its metabolite, sulindac sulfide on modulation of the critical survival kinase, protein kinase B (PKB). Here, we demonstrate for the first time that treatment with either sulindac or sulindac sulfide results in a decrease in PKB activity, and we provide compelling evidence that this occurs through two distinct mechanisms. Additionally, we report that overexpression of, and conditional activation of PKB attenuates the apoptotic effects of sulindac, but not for sulindac sulfide -the metabolic metabolite of sulindac. We also demonstrate that treatment with sulindac sulfide, but not sulindac, results in a very early robust activation of both caspase-8 and -9. Furthermore, we show that the apoptotic effects of sulindac sulfide can be reverted by both the caspase-8 and -9 inhibitors. Evidence is provided to indicate that PKB is targeted by robust caspase activation due to sulindac sulfide. Hence, further investigation into the mechanisms regulating conversion of sulindac to sulindac sulfide (or direct use of the latter compound), may enhance our ability to target cancers with enhanced signaling through the growth factor➝phosphatidylinositol 3-kinase pathway.

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“…Overexpression of ILK is often a prominent feature of human malignancies and its increased abundance in tumor tissues correlates with poor outcome (20)(21)(22)(23)(24). Recent reports suggest that overexpression of ILK in epithelial cells induces the EMT by repressing E-cadherin expression, activating nuclear b-catenin, and inducing a transformed, tumorigenic phenotype (25).…”

Section: Introductionmentioning

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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Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis

Cited by 73 publications

References 39 publications

ILKAP regulates ILK signaling and inhibits anchorage-independent growth

ILKAP regulates ILK signaling and inhibits anchorage-independent growth

Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide

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

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