Sulforaphane blocks hypoxia-mediated resistance to TRAIL-induced tumor cell death.

다국어 초록 (Multilingual Abstract)

<P>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-1관 (HIF-1관) 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-1관 inactivation under hypoxia. This study investigated whether hypoxic inhibition of TRAIL-mediated tumor cell death is increased by SFN-mediated HIF-1관 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-1관 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-1관 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-1관, and also suggests that combination therapy with SFN and TRAIL may provide a novel strategy for treating hypoxic solid tumors.</P>