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Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in

Michela Raimondi1, Fabrizio Fontana1, Monica Marzagalli1

  • 1Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.

Apoptosis : an International Journal on Programmed Cell Death
|April 3, 2021
PubMed

Insights

Delta-tocotrienol (δ-TT) triggers a non-canonical cell death called paraptosis in human melanoma cells. This vitamin E derivative induces mitochondrial dysfunction, leading to cell death and offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Melanoma is an aggressive cancer with limited treatment options.
  • Delta-tocotrienol (δ-TT), a vitamin E derivative, shows anti-cancer effects.
  • Previous studies indicated δ-TT induces apoptosis in melanoma cells.

Purpose of the Study:

  • To investigate if δ-TT can induce paraptosis, a distinct programmed cell death pathway, in human melanoma.
  • To elucidate the mechanisms underlying δ-TT-induced paraptosis.

Main Methods:

  • Treatment of A375 and BLM melanoma cell lines with δ-TT.
  • Assessment of paraptotic features: cytoplasmic vacuolization, endoplasmic reticulum/mitochondrial dilation.
  • Analysis of protein synthesis, MAPK activation, OXPHOS complex I expression, oxygen consumption, mitochondrial membrane potential, ATP synthesis, and AMPK phosphorylation.
  • Measurement of reactive oxygen species (ROS) production and intracellular calcium (Ca2+) levels.
  • Use of IP3R and VDAC inhibitors to explore the relationship between mitochondrial Ca2+ and ROS.

Main Results:

  • δ-TT induced cytoplasmic vacuolization and endoplasmic reticulum/mitochondrial dilation, characteristic of paraptosis.
  • δ-TT treatment reduced OXPHOS complex I, oxygen consumption, ATP synthesis, and AMPK phosphorylation, indicating mitochondrial dysfunction.
  • Mitochondrial dysfunction led to increased ROS production, which was identified as a key mediator of paraptosis.
  • δ-TT disrupted Ca2+ homeostasis, causing mitochondrial Ca2+ overload and activating paraptotic signaling.
  • A direct link between mitochondrial Ca2+ accumulation and ROS generation was established.

Conclusions:

  • δ-TT effectively induces paraptosis in human melanoma cells.
  • The mechanism involves mitochondrial dysfunction, leading to ROS overproduction and Ca2+ dysregulation.
  • These findings highlight δ-TT's potential as a therapeutic agent against melanoma by exploiting non-canonical cell death pathways.
Keywords:
Ca2+ overloadMelanomaMitochondrial impairmentParaptosisROS productionTocotrienols

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