trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway

Sci Rep. 2021 May 14;11(1):10350. doi: 10.1038/s41598-021-89506-8.


trans-Fatty acids (TFAs) are food-derived fatty acids associated with various diseases including cardiovascular diseases. However, the underlying etiology is poorly understood. Here, we show a pro-apoptotic mechanism of TFAs such as elaidic acid (EA), in response to DNA interstrand crosslinks (ICLs) induced by cisplatin (CDDP). We previously reported that TFAs promote apoptosis induced by doxorubicin (Dox), a double strand break (DSB)-inducing agent, via a non-canonical apoptotic pathway independent of tumor suppressor p53 and apoptosis signal-regulating kinase (ASK1), a reactive oxygen species (ROS)-responsive kinase. However, here we found that in the case of CDDP-induced apoptosis, EA-mediated pro-apoptotic action was reversed by knockout of either p53 or ASK1, despite no increase in p53 apoptotic activity. Upon CDDP treatment, EA predominantly enhanced ROS generation, ASK1-p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway activation, and ultimately cell death, all of which were suppressed either by co-treatment of the NADPH oxidase (Nox) inhibitor Apocynin, or by knocking out its regulatory protein, receptor-interacting protein 1 (RIP1). These results demonstrate that in response to CDDP ICLs, TFAs promote p53-dependent apoptosis through the enhancement of the Nox-RIP1-ASK1-MAPK pathway activation, providing insight into the diverse pathogenetic mechanisms of TFAs according to the types of DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / prevention & control
  • Cisplatin / pharmacology
  • DNA Damage / drug effects*
  • Dietary Fats, Unsaturated / adverse effects
  • Dietary Fats, Unsaturated / toxicity*
  • HEK293 Cells
  • Humans
  • MAP Kinase Kinase Kinase 5 / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Mice
  • NADPH Oxidases / antagonists & inhibitors
  • NADPH Oxidases / metabolism
  • Oleic Acids / adverse effects
  • Oleic Acids / toxicity*
  • Oxidation-Reduction
  • RAW 264.7 Cells
  • Reactive Oxygen Species / metabolism
  • Tumor Suppressor Protein p53 / metabolism


  • Acetophenones
  • Dietary Fats, Unsaturated
  • Oleic Acids
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • elaidic acid
  • acetovanillone
  • NADPH Oxidases
  • MAP Kinase Kinase Kinase 5
  • Cisplatin