Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma.

TLDR

NF‑κB activation promotes SCC cell survival and cytokine expression that drive angiogenesis, growth, and metastasis, and its activation involves proteasome‑dependent degradation of IκB. This study evaluated the novel proteasome inhibitor PS‑341 for its ability to block NF‑κB activation and thereby inhibit cell survival, tumor growth, and angiogenesis in murine and human SCC cell lines. PS‑341 suppresses NF‑κB DNA binding and reporter activity at nanomolar concentrations, induces caspase‑mediated apoptosis in SCC cell lines, reduces tumor growth and vascular density in xenografts, and down‑regulates GRO‑α and VEGF, demonstrating inhibition of NF‑κB‑driven survival, proliferation, and angiogenesis.

Abstract

We have shown that activation of nuclear factor-kappa B (NF-kappa B) promotes cell survival and expression of cytokines such as growth-regulated oncogene-alpha, which can modulate angiogenesis, growth, and metastasis of squamous cell carcinoma (SCC). Activation of NF-kappa B and cytoprotective genes in cancer may result from signal-induced phosphorylation and proteasome-dependent degradation of inhibitor-kappa B. In this study, we examined the effects of the novel proteasome inhibitor PS-341 on activation of NF-kappa B and cell survival, growth, and angiogenesis in murine and human SCC cell lines. PS-341 inhibited activation of NF-kappa B DNA binding and functional reporter activity at concentrations between 10(-8) and 10(-7) M. Cytotoxicity was observed at 10(-7) M in four murine and two human SCC lines, and followed early cleavage of poly(ADP-ribose) polymerase, a marker of caspase-mediated apoptosis. In vivo, PS-341 inhibited growth of murine and human SCC in mice at doses of 1--2 mg/kg given three times weekly, and dose-limiting toxicity was encountered at 2 mg/kg. Tumor growth inhibition was associated with a marked decrease in vessel density. PS-341 inhibited expression of the proangiogenic cytokines growth-regulated oncogene-alpha and vascular endothelial growth factor by SCC in the range at which PS-341 inhibits NF-kappa B. We conclude that PS-341 inhibits activation of NF-kappa B pathway components related to cell survival, tumor growth, and angiogenesis in SCC.