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

  • Authors:
    • Jae-Kyo Jeong
    • Myung-Hee Moon
    • Jae-Suk Seo
    • Jae-Won Seol
    • You-Jin Lee
    • Sang-Youel Park
  • View Affiliations

  • Published online on: January 11, 2011     https://doi.org/10.3892/mmr.2011.422
  • Pages: 325-330
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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.

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March-April 2011
Volume 4 Issue 2

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Online ISSN:1791-3004

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Spandidos Publications style
Jeong J, Moon M, Seo J, Seol J, Lee Y and Park S: Sulforaphane blocks hypoxia-mediated resistance to TRAIL-induced tumor cell death. Mol Med Rep 4: 325-330, 2011.
APA
Jeong, J., Moon, M., Seo, J., Seol, J., Lee, Y., & Park, S. (2011). Sulforaphane blocks hypoxia-mediated resistance to TRAIL-induced tumor cell death. Molecular Medicine Reports, 4, 325-330. https://doi.org/10.3892/mmr.2011.422
MLA
Jeong, J., Moon, M., Seo, J., Seol, J., Lee, Y., Park, S."Sulforaphane blocks hypoxia-mediated resistance to TRAIL-induced tumor cell death". Molecular Medicine Reports 4.2 (2011): 325-330.
Chicago
Jeong, J., Moon, M., Seo, J., Seol, J., Lee, Y., Park, S."Sulforaphane blocks hypoxia-mediated resistance to TRAIL-induced tumor cell death". Molecular Medicine Reports 4, no. 2 (2011): 325-330. https://doi.org/10.3892/mmr.2011.422