Abstract 4079: Loss of microtubule-dependent HIF regulation in renal cell carcinoma

Abstract

Abstract Cancer is a class of deadly diseases that is expected to afflict 1 in 2 American men and 1 in 3 American women. Human cancer frequently exhibits hypoxic conditions, which confers resistance to chemotherapy and radiation therapy, and thus prevents patient survival. The master regulator of cellular response to hypoxia is the hypoxia inducible factor 1α (HIF-1α), a transcription factor that drives the expression of genes that promote cell survival, angiogenesis and metabolic adaptation in low oxygen tension conditions. Interestingly, HIF-1α protein stabilization and activation can occur in well-oxygenated tumors that have lost the VHL gene such as clear cell renal cell carcinomas (RCC). As a result RCCs overexpress HIF-1α and several HIF-1 target genes such as the vascular endothelial growth factor VEGF, the glucose transporter GLUT-1 and others resulting in hypervascularity and aggressive tumor phenotypes. HIF-1α upregulation seems to occur even in the earliest detected neoplastic lesions; hence HIF-1α is considered causal to RCC. Therefore, RCCs that are associated with VHL mutations have been proposed as good candidates for HIF-1 targeted therapy. Our laboratory has previously discovered a new mechanism of HIF-1α and HIF-2α regulation that is microtubule dependent. Specifically, we showed that the taxanes and other microtubule targeting drugs (MTDs) inhibit HIF protein and HIF-transcriptional activity downstream of disrupting cellular microtubules. In addition, we have demonstrated that taxane treatment induces the re-localization of HIF-1α mRNA from actively translating to inactively translating ribosomes, as determined by linear sucrose gradients. Interestingly, current data has demonstrated that this mechanism does not occur in RCCs, as taxane treatment fails to inhibit HIF-1α and HIF-2α in VHL-null RCCs at concentrations that affect microtubules. Interestingly, when we used the isogenic RCC2/VHL and RCC4/VHLcells, in which wild-type VHL was stably re-introduced and able to target HIF for degradation, the ability of taxol or other MTDs to inhibit HIF was not restored. RCC with loss of VHL function is the only tumor type, in our experience, in which HIF is unaffected by taxane treatment. These results suggest that the regulation of HIF protein and function has become independent of the microtubule cytoskeleton in and that this mechanism contributes to the excessive HIF stabilization and the chemoresistant nature of RCCs. We are currently investigating whether the lack of drug-induced HIF inhibition in RCC involves changes in HIF regulation at the level of translation or at the level of protein-dependent susceptibility to microtubule dynamics. Further understanding of the failure of this microtubule dependent regulation of HIF-1α in RCC will help us better elucidate the biology of HIF translation and potentially identify new targets for RCC treatment. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4079.