Abstract
BackgroundWe have previously shown that prostate cancer LNCaP cells are resistant to TRAIL, and downregulation of PI-3K/Akt pathway by molecular and pharmacological means sensitizes cells to undergo apoptosis by TRAIL and curcumin. The purpose of this study was to examine the molecular mechanisms by which resveratrol sensitized TRAIL-resistant LNCaP cells.ResultsResveratrol inhibited growth and induced apoptosis in androgen-dependent LNCaP cells, but had no effect on normal human prostate epithelial cells. Resveratrol upregulated the expression of Bax, Bak, PUMA, Noxa, Bim, TRAIL-R1/DR4 and TRAIL-R2/DR5, and downregulated the expression of Bcl-2, Bcl-XL, survivin and XIAP. Treatment of LNCaP cells with resveratrol resulted in generation of reactive oxygen species, translocation of Bax and p53 to mitochondria, subsequent drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, AIF, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and caspase-9 and induction of apoptosis. The ability of resveratrol to sensitize TRAIL-resistant LNCaP cells was inhibited by dominant negative FADD, caspase-8 siRNA or N-acetyl cysteine. Smac siRNA inhibited resveratrol-induced apoptosis, whereas Smac N7 peptide induced apoptosis and enhanced the effectiveness of resveratrol.ConclusionResveratrol either alone or in combination with TRAIL or Smac can be used for the prevention and/or treatment of human prostate cancer.
Highlights
We have previously shown that prostate cancer LNCaP cells are resistant to TRAIL, and downregulation of PI-3K/Akt pathway by molecular and pharmacological means sensitizes cells to undergo apoptosis by TRAIL and curcumin
Resveratrol sensitizes TRAIL-resistant prostate cancer LNCaP cells We have previously shown that TRAIL induces apoptosis in prostate cancer cells with varying sensitivity, and LNCaP cells are resistant to TRAIL [36]
We examined whether resveratrol and/or TRAIL had any effect on human normal prostate epithelial cells (PrEC) (Fig. 1B)
Summary
We have previously shown that prostate cancer LNCaP cells are resistant to TRAIL, and downregulation of PI-3K/Akt pathway by molecular and pharmacological means sensitizes cells to undergo apoptosis by TRAIL and curcumin. The purpose of this study was to examine the molecular mechanisms by which resveratrol sensitized TRAIL-resistant LNCaP cells. Numerous studies have reported interesting properties of resveratrol as a preventive agent against important pathologies i.e. vascular diseases, cancers, viral infection or neurodegenerative processes. Resveratrol acts on the process of carcinogenesis by affecting tumor initiation, promotion and progression, and suppresses the final steps of carcinogenesis, i.e. angiogenesis and metastasis. It induces apoptosis, and cell cycle arrest, and modulates several signal transduction pathways. Despite considerable progress towards our understanding of the signaling pathways leading to resveratrol-mediated apoptosis, the molecular mechanisms by which resveratrol sensitizes prostate cancer cells to TRAIL treatment is not fully understood
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