Farnesyltransferase inhibitor manumycin targets IL1β-Ras-HIF-1α axis in tumor cells of diverse origin.

Abstract

We have recently reported that Ras acts as an intermediate coactivator in IL-1β-mediated hypoxia-inducible factor-1α (HIF-1α) activation in glioblastoma multiforme (GBM). Since HIF-1α plays a crucial role in linking inflammatory and oncogenic pathways, we investigated whether this IL1β-Ras-HIF-1α signaling axis observed in GBM also exists in other tumors of diverse origin under normoxia. Treatment with IL-1β induced Ras in non-GBM cell lines A549 (lung), HeLa (cervical), and HepG2 (liver), and inhibition of Ras activity attenuated HIF-1α activity. Our findings suggest that Ras links IL-1β and HIF-1α 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-1β-mediated HIF-1α activation. Manumycin abrogated IL-1β-induced HIF-1α activation in both glioma and non-glioma tumor cells. In addition, manumycin also decreased IL-1β induced pro-inflammatory responses in tumor cells.

• Authors: Vivek Sharma, Sk Sudipta Shaheen, Deobrat Dixit, Ellora Sen
• Journal: Inflammation (Inflammation) Vol. 35 Issue 2 Pg. 516-9 (Apr 2012) ISSN: 1573-2576 [Electronic] United States
• PMID: 21556735 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Interleukin-1beta
• Polyenes
• Polyunsaturated Alkamides
• Farnesyltranstransferase
• ras Proteins
• manumycin

Topics

• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Farnesyltranstransferase (antagonists & inhibitors)
• HeLa Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, metabolism)
• Interleukin-1beta (physiology)
• Neoplasms (metabolism)
• Polyenes (pharmacology)
• Polyunsaturated Alkamides (pharmacology)
• ras Proteins (biosynthesis, metabolism)