Inhibition of tumor cell invasion and angiogenesis by motuporamines.

Tissue invasion is an important determinant of angiogenesis and metastasis and constitutes an attractive target for cancer therapy. We have developed an assay to identify agents that inhibit invasion by mechanisms other than inhibition of cell attachment or cytotoxicity. A screen of marine sponge extracts identified motuporamines as micromolar inhibitors of invasion of basement membrane gels by MDA-231 breast carcinoma, PC-3 prostate carcinoma, and U-87 and U-251 glioma cells. Motuporamine C inhibits cell migration in monolayer cultures and impairs actin-mediated membrane ruffling at the leading edge of lamellae. Motuporamine C also reduces beta1-integrin activation, raising the possibility that it interferes with "inside-out" signaling to integrins. In addition, motuporamine C inhibits angiogenesis in an in vitro sprouting assay with human endothelial cells and an in vivo chick chorioallantoic membrane assay. The motuporamines show little or no toxicity or inhibition of cell proliferation, and they are structurally simple and easy to synthesize, making them attractive drug candidates.

Signaling pathways mediated by tumor necrosis factor alpha.

Tumor necrosis factor alpha (TNFalpha) has been shown to trigger many signaling pathways. Following oligomerization by TNFalpha, the receptors TNF-RI and TNF-RII associate with adapter molecules via specific protein-protein interactions. The subsequent recruitment of downstream molecules to the receptor complex enables propagation of the TNFalpha signal. Two cellular responses to TNFalpha have been well documented, the induction of cell death and the activation of gene transcription for cell survival. TNFalpha-induced apoptosis involves the activation of caspase cascades, which culminate in the cleavage of specific cellular substrates to effect cell death. TNFalpha has also been implicated in various caspase-independent cell death processes. Two transcription factors activated by TNFalpha are nuclear factor kappaB (NFkappaB) and activating protein 1 (AP-1). Pathways that promote the activation of these transcription factors involve signaling molecules such as kinases, phospholipases, and sphingomyelinases. In addition to increased survival (anti-apoptotic) gene expression, NFkappaB and AP-1 also induce the expression of genes involved in inflammation, cell growth, and signal regulation. The past decade has witnessed the identification of numerous signaling intermediates implicated in TNFalpha cellular responses. This article reviews the molecular mechanisms of TNFalpha signal transduction. In particular, pathways involved in cell death and transcription factor activation are discussed.