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C-27-carboxylated oleanane triterpenoids up-regulate TRAIL DISC assembly via p38 MAPK and CHOP-mediated DR5

Hee Sun Byun1, Wei Zhou2, InWha Park3

  • 1Department of Pharmacology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Daejeon 35015, Republic of Korea.

Biochemical Pharmacology
|October 26, 2018
PubMed

Insights

Novel C-27-carboxylated oleanolic acid derivatives (C27OAs) from Astilbe rivularis enhance TRAIL-induced apoptosis. These compounds selectively sensitize glioblastoma cells by upregulating death receptor 5 (DR5) and DISC formation, offering a new strategy for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Targeting TNF-related apoptosis-inducing ligand (TRAIL) for cancer therapy faces challenges, particularly in glioblastoma, due to impaired death-inducing signaling complex (DISC)-mediated caspase-8 activation.
  • Existing treatments often struggle with resistance mechanisms in highly malignant tumors.

Purpose of the Study:

  • To identify novel compounds that can sensitize cancer cells to TRAIL-induced apoptosis.
  • To elucidate the mechanism by which these sensitizers function, focusing on glioblastoma.

Main Methods:

  • Screening of Astilbe rivularis constituents for TRAIL-sensitizing activity.
  • Investigating the effects of identified compounds on cell surface death receptor expression and DISC formation.
  • Analyzing the molecular pathways involved in the sensitization process, including MAPK and transcription factor activation.

Main Results:

  • C-27-carboxylated oleanolic acid derivatives (C27OAs) were identified as potent TRAIL sensitizers.
  • C27OAs selectively enhanced TRAIL-mediated apoptosis by upregulating death receptor 5 (DR5) and promoting DISC assembly.
  • The mechanism involves p38 MAPK pathway-dependent transactivation of C/EBP homology protein, independent of p53 or intracellular reactive oxygen species.

Conclusions:

  • C27OAs represent a novel class of TRAIL sensitizers that target the upstream DISC assembly.
  • These compounds offer a promising therapeutic strategy for overcoming TRAIL resistance in glioblastoma.
  • Further development of C27OAs could facilitate TRAIL-based chemotherapy for glioblastoma patients.
Keywords:
C-27-carboxylated oleanolic acids (C27OAs)Caspase-8DISC-mediated apoptosisDeath receptorTRAIL resistance

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