Farnesyltransferase Inhibitor Manumycin Targets IL1β-Ras-HIF-1α Axis in Tumor Cells of Diverse Origin

We have recently reported that Ras acts as an intermediate coactivator in IL-1 beta-mediated hypoxia-inducible factor-1 alpha (HIF-1 alpha) activation in glioblastoma multiforme (GBM). Since HIF-1 alpha plays a crucial role in linking inflammatory and oncogenic pathways, we investigated whether this IL1 beta-Ras-HIF-1 alpha signaling axis observed in GBM also exists in other tumors of diverse origin under normoxia. Treatment with IL-1 beta induced Ras in non-GBM cell lines A549 (lung), HeLa (cervical), and HepG2 (liver), and inhibition of Ras activity attenuated HIF-1 alpha activity. Our findings suggest that Ras links IL-1 beta and HIF-1 alpha in tumors of diverse origin. As we have previously reported that the farnesyltransferase inhibitor manumycin decreases Ras activity in glioma cells, we investigated whether manumycin could regulate IL-1 beta-mediated HIF-1 alpha activation. Manumycin abrogated IL-1 beta-induced HIF-1 alpha activation in both glioma and non-glioma tumor cells. In addition, manumycin also decreased IL-1 beta induced pro-inflammatory responses in tumor cells.