THE ROLE OF THE IKKbeta KINASE IN K-RAS-INDUCED ANGIOGENESIS.

Abstract

The most frequent genetic changes found in lung tumors are activating point mutations in the K-Ras gene, which have been causally linked to the oncogenic process. Unfortunately, different approaches to directly target Ras proteins for therapy have sofar been unsuccessful. Therefore, in order to select better targets for lung cancer therapy, it will be necessary to identify K-Ras downstream pathways involved in the establishment of critical oncogenic characteristics. One of the critical characteristics required for tumors to grow and progress is the ability of tumor cells to drive angiogenesis. Therefore, the main goal of this proposal is to identify therapeutic targets involved in tumor angiogenesis induced by K-Ras in lung cancer. Based on the fact that Ras proteins promote angiogenesis by inducing expression of interleukin 8 (IL-8), we hypothesize that (1) the induction of IL-8 by K-Ras (and the pro-angiogenic effects of this cytokine) is mediated by IKK² kinase and (2) that inhibition of IKK² will reduce tumor angiogenesis in vitro and tumor growth in vivo. This hypothesis has been formulated on the basis of previous studies showing that the main IKK² substrate, the transcription factor NF-ºB, is able to promote angiogenesis and metastasis in different tumor models, that K-Ras activates NF-ºB in an IKK²-dependent manner, and that inhibition of IKK² activity with a pharmacological inhibitor in K-Ras transformed lung cells reduces the expression of IL-8. The rationale that governs this proposal is that we expect to elucidate the molecular mechanism involved in K-Ras-mediated IL-8 induction, angiogenesis and tumor progression. Furthermore, we expect to validate new strategies to develop anti-tumor therapies.