Integrin-linked kinase: a cancer therapeutic target unique among its ILK

Abstract

Cancer development requires the acquisition of several capabilities that include increased replicative potential, anchorage and growth-factor independence, evasion of apoptosis, angiogenesis, invasion of surrounding tissues and metastasis. One protein that has emerged as promoting many of these phenotypes when dysregulated is integrin-linked kinase (ILK), a unique intracellular adaptor and kinase that links the cell-adhesion receptors, integrins and growth factors to the actin cytoskeleton and to a range of signalling pathways. The recent findings of increased levels of ILK in various cancers, and that inhibition of ILK expression and activity is antitumorigenic, makes ILK an attractive target for cancer therapeutics.

Integrin signalling adaptors: not only figurants in the cancer story

“…ILK has been described to be involved in all aspects of cancer cell progression. ILK overexpression in epithelial cells leads to cell transformation, invasion, and acquisition of survival and mesenchymal properties, supporting a role for ILK as an oncogene 31 . In mammary epithelial cells, ILK overexpression triggers EMT, characterized by loss of E-CADHERIN and -CATENIN in adherence junctions and -CATENIN accumulation in the nucleus, leading to increased synthesis and deposition of fibronectin, further supporting the ILKdependent EMT 100 .…”

“…The expression of ILK has been analysed in a large number of human malignancies [29][30][31] and is often found to be elevated and associated with tumour progression and shortened survival (Table 1). Increased ILK expression has been associated with more differentiated areas of malignant gastrointestinal, renal, neural and bone marrow tumours, suggesting that ILK might be also an indicator of differentiation 29,32 .…”

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

“…ILK is the binding partner of integrin, associating with the cytoplasmic domain of integrin b1 and mediating integrin-dependent cell attachment (Hannigan et al, 1996). Inhibition of ILK activity or expression results in the inhibition of cell adhesion by its downstream signaling to protein kinase B/Akt and glycogen synthase kinase-3b (Cordes and van Beuningen, 2003;Hannigan et al, 2005)…”

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

“…The integrin-linked kinase (ILK) is a modular protein with separate scaffolding and kinase-like domains that mediates the physical and functional coupling of integrins to growth factor signaling (Hannigan et al, 2005;McDonald et al, 2008a). ILK modulates integrinmediated adhesion by directly interacting with the cytoplasmic tails of b1-or b3-integrin receptors (Hannigan et al, 1996), and complexes with Parvin A/B (Attwell et al, 2003;Mongroo et al, 2004) and PINCH (Tu et al, 1999).…”

“…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).…”