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Ca 2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

Authors
  • Raimondi, Michela1
  • Fontana, Fabrizio1
  • Marzagalli, Monica1
  • Audano, Matteo1
  • Beretta, Giangiacomo1
  • Procacci, Patrizia1
  • Sartori, Patrizia1
  • Mitro, Nico1
  • Limonta, Patrizia1
  • 1 Università degli Studi di Milano,
Type
Published Article
Journal
APOPTOSIS
Publisher
Springer-Verlag
Publication Date
Apr 03, 2021
Volume
26
Issue
5-6
Pages
277–292
Identifiers
DOI: 10.1007/s10495-021-01668-y
PMID: 33811561
PMCID: PMC8197726
Source
PubMed Central
Keywords
Disciplines
  • Article
License
Unknown

Abstract

Abstract Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for paraptosis induction. Additionally, δ-TT caused Ca2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated paraptosis. Graphic Abstract δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.

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