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ShDcR3 sensitizes TRAIL-resistant HCC cells by inducing caspase-dependent apoptosis while suppressing NF-κB dependent

Dong-Yu Liang1,2, Wei Huang3, Qing Chang2

  • 1Department of Central Laboratory, Songjiang Hospital Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.

Plos One
|February 15, 2018
PubMed

Insights

Hepatocellular carcinoma (HCC) cells resist tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) therapy. Silencing Decoy receptor 3 (DcR3) enhances TRAIL-induced apoptosis in HCC cells by inhibiting the NF-κB pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • Hepatocellular carcinoma (HCC) exhibits resistance to apoptosis-inducing therapies like tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL).
  • The molecular mechanisms driving this TRAIL resistance in HCC remain incompletely understood.
  • Decoy receptor 3 (DcR3) is implicated in cancer progression and immune evasion.

Purpose of the Study:

  • To investigate the role of Decoy receptor 3 (DcR3) in TRAIL-mediated apoptosis resistance in HCC cells.
  • To elucidate the molecular pathways through which DcR3 influences TRAIL sensitivity.
  • To evaluate the therapeutic potential of targeting DcR3 to enhance TRAIL-induced apoptosis in HCC.

Main Methods:

  • Utilized lentiviral vectors with short hairpin RNA (shRNA) to downregulate DcR3 expression in Huh7 HCC cells.
  • Assessed apoptosis induction using TRAIL treatment in DcR3-silenced and control cells.
  • Analyzed the expression of key apoptotic regulators, transcription factors (NF-κB), and related proteins (cFLIPL) using molecular assays.
  • Investigated the involvement of caspase-dependent pathways and the IκB kinase (IKK) pathway.

Main Results:

  • Downregulation of DcR3 significantly enhanced TRAIL-mediated apoptosis and reduced proliferation in Huh7 cells.
  • Silencing DcR3 upregulated pro-apoptotic proteins (Bid, caspase-3, caspase-8) and increased caspase-dependent cell death.
  • DcR3 knockdown inhibited TRAIL-induced nuclear factor κB (NF-κB) activation via the IκB kinase (IKK) pathway and suppressed cFLIPL expression.
  • cFLIPL silencing mimicked the cytotoxic effects of DcR3 knockdown, while its overexpression blocked TRAIL/shDcR3-induced apoptosis.

Conclusions:

  • Decoy receptor 3 (DcR3) plays a critical role in conferring resistance to TRAIL-induced apoptosis in hepatocellular carcinoma (HCC).
  • Silencing DcR3 sensitizes HCC cells to TRAIL by inhibiting the NF-κB signaling pathway and downregulating cFLIPL.
  • Targeting DcR3 represents a promising strategy to overcome TRAIL resistance in HCC treatment.

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