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Involvement of PAR-4 in cannabinoid-dependent sensitization of osteosarcoma cells to TRAIL-induced apoptosis

Antonietta Notaro1, Selenia Sabella1, Ornella Pellerito2

  • 11. Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Polyclinic, Palermo, Italy.

International Journal of Biological Sciences
|May 6, 2014
PubMed

Insights

The synthetic cannabinoid WIN 55,212-2 triggers cell cycle arrest and endoplasmic reticulum stress in osteosarcoma cells. While not inducing apoptosis directly, it primes cells for TRAIL-mediated death, suggesting anticancer potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Synthetic cannabinoids, like WIN 55,212-2, are potent cannabinoid receptor agonists.
  • These compounds exhibit potential anticancer properties warranting further investigation.
  • Osteosarcoma remains a challenging malignancy with a need for novel therapeutic strategies.

Purpose of the Study:

  • To investigate the effects of WIN 55,212-2 on human osteosarcoma cell lines (MG63 and Saos-2).
  • To determine the impact of WIN 55,212-2 on cell proliferation, cell cycle distribution, and programmed cell death.
  • To elucidate the underlying molecular mechanisms, including endoplasmic reticulum stress and autophagy.

Main Methods:

  • Treatment of MG63 and Saos-2 cells with WIN 55,212-2.
  • Analysis of cell cycle distribution using flow cytometry.
  • Assessment of endoplasmic reticulum stress markers (GRP78, CHOP, TRB3).
  • Evaluation of autophagy markers (LC3-I/II conversion, monodansylcadaverine, acridine orange staining).
  • Morphological analysis of treated cells.
  • Investigation of apoptotic pathways and the role of PAR-4 and TRAIL.

Main Results:

  • WIN 55,212-2 induced G2/M cell cycle arrest in osteosarcoma cells.
  • Treatment led to the upregulation of endoplasmic reticulum stress markers (GRP78, CHOP, TRB3).
  • Evidence of autophagy induction was observed, including LC3-II conversion and autolysosome formation.
  • Morphological changes included increased cell size and cytoplasmic vacuolization.
  • WIN 55,212-2 did not induce canonical apoptosis but increased PAR-4 levels and GRP78 cell surface translocation.
  • Co-treatment with TRAIL enhanced WIN 55,212-2-induced apoptotic death.

Conclusions:

  • WIN 55,212-2 exhibits anticancer effects in osteosarcoma cells by inducing cell cycle arrest, ER stress, and autophagy.
  • The compound modulates pathways that sensitize cells to TRAIL-induced apoptosis, suggesting a potential therapeutic role.
  • Further research into WIN 55,212-2 as a component of osteosarcoma treatment is warranted.
Keywords:
CannabinoidsER stressGRP78/PAR-4 complex.TRAILautophagyosteosarcoma cells

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