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Poly-ADP-ribosylation of HMGB1 regulates TNFSF10/TRAIL resistance through autophagy

Minghua Yang1, Liying Liu, Min Xie

  • 1a Department of Pediatrics; Xiangya Hospital ; Central South University ; Changsha , Hunan China.

Autophagy
|January 22, 2015
PubMed

Insights

Poly (ADP-ribose) polymerase 1 (PARP1) regulates high mobility group box 1 (HMGB1) in cancer cells, influencing autophagy and apoptosis. This pathway impacts sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TNFSF10/TRAIL) therapy.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Apoptosis and autophagy are key cell death pathways with crosstalk influencing cancer drug response.
  • The precise mechanisms governing this crosstalk, particularly in response to specific cancer therapies, remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of high mobility group box 1 (HMGB1) in tumor necrosis factor [ligand] superfamily, member 10 (TNFSF10)-induced cancer cell death.
  • To investigate the involvement of poly [ADP-ribose] polymerase 1 (PARP1) in regulating HMGB1-mediated cell death pathways.

Main Methods:

  • Investigated the role of PARP1 in TNFSF10-induced cancer cell death using pharmacological inhibition and gene knockdown.
  • Assessed HMGB1 ADP-ribosylation, cytoplasmic translocation, and complex formation with BECN1.
  • Evaluated the impact of modulating the PARP1-HMGB1 pathway on autophagy, apoptosis, and TNFSF10 anticancer activity in vitro and in vivo.

Main Results:

  • PARP1 activation was essential for TNFSF10-induced HMGB1 ADP-ribosylation and subsequent cytoplasmic translocation.
  • Inhibition or knockdown of PARP1 reduced HMGB1-BECN1 complex formation, diminished autophagy, and increased apoptosis.
  • Suppression of the PARP1-HMGB1 pathway enhanced the anticancer efficacy of TNFSF10.

Conclusions:

  • PARP1 is a critical upstream regulator of HMGB1-mediated autophagy in cancer cells.
  • The PARP1-HMGB1 axis plays a key role in maintaining the balance between apoptosis and autophagy.
  • Understanding this pathway offers new insights into mechanisms of TNFSF10 resistance and potential therapeutic strategies.
Keywords:
ATG, autophagy-relatedDISC, death-inducing signaling complexHMGB1HMGB1, high mobility group box 1MAP1LC3A/LC3, microtubule-associated protein 1 light chain 3 αPARP-1PARP1, poly (ADP-ribose) polymerase 1PARylation, poly-ADP-ribosylationRIPK1/RIP, receptor (TNFRSF)-interacting serine-threonine kinase 1TNF, tumor necrosis factorTNFSF10/TRAIL, tumor necrosis factor (ligand) superfamily, member 10TRAILTUNEL, TdT-mediated dUTP-X nick end labelingapoptosisautophagyshRNA, short hairpin RNA

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