title: 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.affiliation: National Brain Research Centre, Manesar, Haryana 122 050, India.
authors.forename: Vivek
authors.initials: V
authors.lastname: Sharma
authors.forename: Sk Sudipta
authors.initials: SS
authors.lastname: Shaheen
authors.forename: Deobrat
authors.initials: D
authors.lastname: Dixit
authors.forename: Ellora
authors.initials: E
authors.lastname: Sen
mesh_terms: D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000378:metabolism*; D053583:Interleukin-1beta / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism*; D011090:Polyenes / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D018631:ras Proteins / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D051231:Farnesyltranstransferase; D018631:ras Proteins; C054474:manumycin