Integrin-linked kinase, a promising cancer therapeutic target: biochemical and biological properties.

Integrin-linked kinase (ILK) is an ankyrin repeat-containing Ser/Thr kinase that interacts with the cytoplasmic domains of beta(1) and beta(3) integrins. ILK is widely expressed in tissues throughout the body, and, as might be expected, appears to mediate a diversity of functions relating to its role in coupling integrins and growth factor receptors to downstream signaling pathways. Through its downstream targets protein kinase B/Akt and glycogen synthase kinase-3beta, ILK appears to be involved in several oncogenesis-related events, including suppression of apoptosis and promotion of cell survival, as well as cell migration and invasion. Over-expression of ILK in epithelial cells results in anchorage-independent cell growth with increased cell cycle progression. Inoculation of nude mice with ILK over-expressing cells leads to tumor formation. Furthermore, increased ILK expression and activity have been correlated with malignancy in several human tumor types, including breast, prostate, brain, and colon carcinomas. Based on these findings, ILK represents an excellent therapeutic target for the prevention of tumor progression. Here, we provide an overview of the physical and biochemical properties of ILK, and present data describing the impact of small-molecule ILK inhibitors on several ILK-mediated cellular functions.

Cytomegalovirus-caused release of collagenase IV from human cerebral microvascular endothelial cells.

BACKGROUND: Human cytomegalovirus (HCMV) in most normal individuals results in an asymptomatic infection, but under some circumstances, such as in the transplant setting, AIDS and intrauterine infection of the fetus, HCMV infection can lead to more serious consequences, including central nervous system infection. Recently it has been demonstrated that HCMV-infected endothelial cells can be detected in the circulation; however, no mechanism has been suggested. OBJECTIVE: To determine whether HCMV infection of confluent human microvascular endothelial cells (HMEC) in culture results in the induction of type IV collagenase. This would provide a mechanism by which HCMV-infected HMECs could be released into the circulation. STUDY DESIGN: Confluent cultures of brain-derived HMECs were infected with HCMV and culture supernatants were sampled for collagenase IV, general protease and viral titers. RESULTS: HCMV infection of HMECs stimulated a significant release of collagenase type IV activity which peaked early in the assay within 3-5 days and fell off rapidly thereafter. This stimulation of protease activity differed only slightly between non-infected and infected cultures. By day 6, viral cytopathic effects became evident and HCMV titers reached approximately 5 x 10(5) PFU/ml by day 9. CONCLUSIONS: These results demonstrate that HCMV infection of HMEC induces the release of collagenase type IV. This may lead to the degradation of the basement membrane and subsequently to the release of fully infected endothelial cells into the circulation resulting in further dissemination of the infection.

Inhibition of angiogenesis and growth of human non-malignant and malignant meningiomas by TNP-470.

Meningiomas are relatively common (22%) vascular brain tumors. 3-11% of meningiomas are malignant, and defy currently available therapy. Inhibition of neovascularization is one potential strategy for treating these hypervascular tumors. Inhibition of tumor-induced angiogenesis by TNP-470 (previously termed AGM-1470), a synthetic analogue of fumagillin, was tested on the growth of human non-malignant and malignant meningiomas in nude mice. TNP-470 significantly inhibited tumor neovascularization and tumor growth of both non-malignant and malignant meningiomas. TNP-470 is now in human trial and should be tested for efficacy in treating malignant or recurrent aggressive meningiomas.