title: Sulforaphane blocks hypoxia-mediated resistance to TRAIL-induced tumor cell death.
abstract: Hypoxia occurs frequently in various solid tumors and elicits a cellular response designed to improve cell survival through adaptive processes, thereby accelerating cancer progression and the development of chemotherapy resistance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, leads to tumor cell death via both intrinsic and extrinsic apoptotic signaling pathways. Hypoxia inhibits TRAIL-mediated apoptosis and attenuates the therapeutic activity of TRAIL in cancer management. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in tumor hypoxia by up-regulating gene expression related to angiogenesis, cancer invasion and anti-apoptosis. Sulforaphane (SFN), a phenethyl isothiocyanate, elicits HIF-1α inactivation under hypoxia. This study investigated whether hypoxic inhibition of TRAIL-mediated tumor cell death is increased by SFN-mediated HIF-1α instability. SFN induced cell death in various tumor cells, including SK-N-SH, SNU-638, HeLa and A549 cells, and showed cell cytotoxicity in hypoxia-exposed tumor cells. Western blot analysis showed that SFN treatment increased p53 and activated caspase-3 proteins, and decreased HIF-1α activation under hypoxia. Under low-oxygen conditions, TRAIL-treated cells displayed inhibited apoptosis, while SFN-pre-treated cells exhibited stronger sensitization to TRAIL under the hypoxic conditions. SFN treatment enhanced TRAIL-induced activation of proteins, including caspase-3 and p53. SFN dose-dependently decreased HIF-1α protein levels in cancer cells, which was mediated by decreased protein stability. This study demonstrated that SFN recovered hypoxia-mediated resistance to TRAIL via instability of HIF-1α, and also suggests that combination therapy with SFN and TRAIL may provide a novel strategy for treating hypoxic solid tumors.
authors.affiliation: Chonbuk National University, Center for Healthcare Technology Development, Bio-Safety Research Institute, College of Veterinary Medicine, Jeonju, Jeonbuk 561-756, Korea.
authors.forename: Jae-Kyo
authors.initials: JK
authors.lastname: Jeong
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Moon
authors.forename: Jae-Suk
authors.initials: JS
authors.lastname: Seo
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Seol
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Sang-Youel
authors.initials: SY
authors.lastname: Park
mesh_terms: D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D017879:Isothiocyanates; D009369:Neoplasms / Q000473:pathology*; D010100:Oxygen / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013454:Sulfoxides; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013861:Thiocyanates / Q000494:pharmacology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017879:Isothiocyanates; D013454:Sulfoxides; D053221:TNF-Related Apoptosis-Inducing Ligand; D013861:Thiocyanates; C016766:sulforaphane; D010100:Oxygen