Preferential Dependence of Breast Cancer Cells versus Normal Cells on Integrin-Linked Kinase for Protein Kinase B/Akt Activation and Cell Survival

Troussard, Armelle; McDonald, Paul C.; Wederell, Elizabeth D.; Mawji, Nasrin M.; Filipenko, Nolan R.; Gelmon, Karen A.; Kucab, Jill E.; Dunn, Sandra E.; Emerman, Joanne T.; Bally, Marcel B.; Dedhar, Shoukat

doi:10.1158/0008-5472.can-05-2304

Cited by 114 publications

(140 citation statements)

References 53 publications

(66 reference statements)

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“…Transient transfection of wild-type ILK (ILK-WT) increased Tcf/ Lef transcriptional activity over Wnt3a alone (Figure 2a), whereas transfection of ILK-DN reduced the Wnt3a-induced activation of this transcription factor in a dose-dependent manner (Figure 2a). ILK activity was also inhibited by treatment with a second generation of a highly selective small molecule ILK inhibitor, QLT-0267 (Zhou et al, 2004), which inhibits ILK kinase activity in a dose-dependent manner (Troussard et al, 2006). We have recently shown the specificity of this ILK inhibitor in another study by overexpressing a constitutively active mutant of ILK in the presence of QLT-0267, and showing that this active ILK rescued the effect of the inhibitor (Troussard et al,…”

Section: Resultsmentioning

confidence: 99%

Modulation of Wnt3a-mediated nuclear β-catenin accumulation and activation by integrin-linked kinase in mammalian cells

2006

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The Wnt gene family encodes secreted signaling molecules that play important roles in tumorgenesis and embryogenesis. The canonical Wnt signaling pathway regulates target gene expression via the stabilization and nuclear translocation of the cytoplasmic pool of b-catenin. The activation of integrin-linked kinase (ILK) is also known to regulate the stabilization and subsequent nuclear translocation of b-catenin in several epithelial cell models. We now report that molecular and pharmacological inhibition of ILK activity in mammalian cells directly modulates Wnt signaling by suppressing the stabilization and nuclear translocation of b-catenin, as well as b-catenin/Lefmediated transcription. Inhibition of ILK activity, but not phosphatidylinositol-3 kinase (PI3K) or MEK activities suppresses nuclear b-catenin stabilization in cells stably expressing Wnt3a as well as in cells exposed to either Wnt3a conditioned media or purified Wnt3a. Furthermore, ILK inhibition reverses the Wnt3a-induced suppression of b-catenin phosphorylation that accompanies b-catenin stabilization. In addition, we show that ILK can be identified in a complex with Wnt pathway components such as adenomatous polyposis coli and GSK-3. Upon treatment of L cells with Wnt3a-CM, glycogen synthase kinase-3 (GSK-3b) becomes highly phosphorylated on Ser 9, which is completely abolished upon inhibition of ILK activity. However, acute exposure of L cells to purified Wnt3a does not result in the stimulation of GSK-3b Ser 9 phosphorylation, despite b-catenin stabilization. Together our data demonstrate that ILK activity can modulate acute Wnt3a mediated b-catenin phosphorylation, stabilization and nuclear activation in a PI3K-independent manner, as well as the more prolonged PI3K-dependent secondary effects of Wnt signaling on GSK-3 phosphorylation. Finally, we suggest that a novel small molecule inhibitor of ILK, QLT-0267, may be a useful tool in the regulation of pathological Wnt signaling.

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Section: Resultsmentioning

confidence: 99%

Modulation of Wnt3a-mediated nuclear β-catenin accumulation and activation by integrin-linked kinase in mammalian cells

2006

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“…One small molecule inhibitor that has been used to target ILK is QLT0267. This second-generation ILK inhibitor inhibits the kinase activity of ILK and it exhibits a high degree of selectivity against a wide panel of protein kinases (Troussard et al, 2006). Using this in vitro invasion assay, we showed incubation of the tumor cells with 10 mM QLT0267 impaired invasion into the collagen I gel (Figure 5e).…”

Section: Pharmacological Inhibition Of Ilk In Established Erbb2 Tumormentioning

confidence: 93%

“…Whereas ILK-induced AKT phosphorylation on its serine residue S473 increases cell survival by promoting anoikis resistance , phosphorylation of this residue also induces VEGF-dependent angiogenesis in cancer cell lines (Tan et al, 2004). Conversely, inhibition of ILK or ILK-PINCH function markedly decreases AKT phosphorylation in number of normal and cancer cell lines (Persad et al, 2000;Fukuda et al, 2003aFukuda et al, , 2003bHannigan et al, 2005;Koul et al, 2005;Younes et al, 2005;Troussard et al, 2006). Recent data have also shown that ILK functionally interacts with mTORC2 (Troussard et al, 2006), through a direct interaction with Rictor, a component of the mTOR complex 2 (McDonald et al, 2008b).…”

Section: Introductionmentioning

confidence: 99%

Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer

et al. 2010

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Elevated expression of the integrin-linked kinase (ILK) has been observed in a variety of cancers and has been further correlated with poor clinical outcome. Here, we show that mammary epithelial disruption of ILK results in a profound block in mammary tumor induction. Consistent with these observations, inhibition of ILK function in ErbB2-expressing cells with small molecule inhibitor or RNA interference resulted in profound block in their in vitro invasive properties due to the induction of apoptotic cell death. The rare ILK-deficient tumors that eventually arose overcame this block in tumor induction by an upregulation of ErB3 phosphorylation. These observations provide direct evidence that ILK has a critical role in the initiation phase of ErbB2 tumor induction.

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“…About 1.4% of breast cancers also contain a mutation in AKT1 (E17 K) that confers constitutive activity (Carpten et al, 2007;Stemke-Hale et al, 2008). Other regulators, 3-phosphoinositidedependent protein kinase 1 (PDK1) or integrin-linked kinase (ILK) activate AKT1 by inducing phosphorylation of S308 or S473 (Lawlor and Alessi, 2001;Troussard et al, 2006). The role of PDK1 or ILK in the mechanisms of resistance to trastuzumab is not known at present.…”

Section: Regulation Of Akt1mentioning

confidence: 99%

Calpain regulates sensitivity to trastuzumab and survival in HER2-positive breast cancer

et al. 2009

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Resistance to anti-HER2 (human epithelial growth factor receptor 2) trastuzumab therapy occurs commonly in HER2-positive breast cancer and involves overactivation of HER2 and/or AKT1. Using the model of trastuzumabsensitive or trastuzumab-resistant HER2-positive cells with wild-type PTEN, negative regulator of AKT1, we explore the involvement of cysteine protease calpain in mechanisms of trastuzumab resistance. Overexpression of calpain1 or activation of endogenous calpain during adhesion or trastuzumab treatment of trastuzumabsensitive cells induces cleavage of cytoplasmic domains of HER2/phospho-HER2; cleavage occurs in HER2-positive tumors. Expression of the catalytically inactive mutant of calpain1 reduces the cleavage to enhance the activity of HER2, inactivates PTEN to enhance the activation of AKT1, induces desensitization to trastuzumab and promotes survival of trastuzumab-sensitive cells. In the model of trastuzumab resistance, constitutive overactivation of HER2 and AKT1 correlates with reduced activation of calpain. Moreover, inhibitors of the catalytic site of calpain reduce the increase in constitutive activity of AKT1 and survival of trastuzumab-resistant cells selectively. Together, by regulating the activation of HER2 and PTEN/AKT1, calpain regulates trastuzumab sensitivity and survival, and the deregulation of the activation of calpain promotes trastuzumab resistance. Trastuzumab-resistant cells activate AKT1 in a mechanism dependent on the residual calpain activity, inhibition of which restores trastuzumab sensitivity and rescues resistance. These data identify calpain as a new therapeutic target in HER2-positive breast cancer.

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Preferential Dependence of Breast Cancer Cells versus Normal Cells on Integrin-Linked Kinase for Protein Kinase B/Akt Activation and Cell Survival

Cited by 114 publications

References 53 publications

Modulation of Wnt3a-mediated nuclear β-catenin accumulation and activation by integrin-linked kinase in mammalian cells

Modulation of Wnt3a-mediated nuclear β-catenin accumulation and activation by integrin-linked kinase in mammalian cells

Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer

Calpain regulates sensitivity to trastuzumab and survival in HER2-positive breast cancer

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