Aconitase 2 sensitizes MCF-7 cells to cisplatin eliciting p53-mediated apoptosis in a ROS-dependent manner

Fabio Ciccarone, Pamela De Falco, Maria Rosa Ciriolo

Research output: Contribution to journalArticlepeer-review

Abstract

Aconitase 2 (ACO2) belongs to the tricarboxylic acid (TCA) cycle, which represents a key metabolic hub for cellular metabolism that is frequently altered in cancer for satisfying bioenergetic and biosynthetic requirements of proliferating cells. The promotion of ACO2 activity in breast cancer cell lines was shown to slow down proliferation imposing a switch from aerobic glycolysis to oxidative metabolism. The alteration of metabolic pathways in cancer also impinges on the sensitivity to chemotherapeutic interventions. In this work, we evidence that the presence of ACO2 sensitizes cells to the treatment with the genotoxic agents cisplatin (CDDP) and doxorubicin activating the apoptotic cell death mechanism. This response was driven by the accumulation of reactive oxygen species (ROS) following both ACO2 overexpression and CDDP exposure that permit the stabilization/activation of p53 in nuclear and mitochondrial compartments. Collectively, our results highlight that in ACO2 overexpressing cells the promotion of mitochondrial metabolism accounts for increased ROS production that was buffered by p53 mitochondrial recruitment and autophagy induction. However, these systems are not able to counteract the CDDP-mediated oxidative stress that becomes the Achilles heel for increasing susceptibility to apoptotic cell death.

Original languageEnglish
Article number114202
Pages (from-to)2-10
JournalBiochemical Pharmacology
Volume180
DOIs
Publication statusPublished - Oct 2020

Keywords

  • Autophagy
  • Cisplatin
  • Mitochondria
  • Oxidative stress
  • TCA cycle

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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