Receptor-interacting protein 1 increases chemoresistance by maintaining inhibitor of apoptosis protein levels and reducing reactive oxygen species through a microRNA-146a-mediated catalase pathway

J Biol Chem. 2014 Feb 28;289(9):5654-63. doi: 10.1074/jbc.M113.526152. Epub 2014 Jan 14.


Although receptor-interacting protein 1 (RIP1) is well known as a key mediator in cell survival and death signaling, whether RIP1 directly contributes to chemotherapy response in cancer has not been determined. In this report, we found that, in human lung cancer cells, knockdown of RIP1 substantially increased cytotoxicity induced by the frontline anticancer therapeutic drug cisplatin, which has been associated with robust cellular reactive oxygen species (ROS) accumulation and enhanced apoptosis. Scavenging ROS dramatically protected RIP1 knockdown cells against cisplatin-induced cytotoxicity. Furthermore, we found that, in RIP1 knockdown cells, the expression of the hydrogen peroxide-reducing enzyme catalase was dramatically reduced, which was associated with increased miR-146a expression. Inhibition of microRNA-146a restored catalase expression, suppressed ROS induction, and protected against cytotoxicity in cisplatin-treated RIP1 knockdown cells, suggesting that RIP1 maintains catalase expression to restrain ROS levels in therapy response in cancer cells. Additionally, cisplatin significantly triggered the proteasomal degradation of cellular inhibitor of apoptosis protein 1 and 2 (c-IAP1 and c-IAP2), and X-linked inhibitor of apoptosis (XIAP) in a ROS-dependent manner, and in RIP1 knockdown cells, ectopic expression of c-IAP2 attenuated cisplatin-induced cytotoxicity. Thus, our results establish a chemoresistant role for RIP1 that maintains inhibitor of apoptosis protein (IAP) expression by release of microRNA-146a-mediated catalase suppression, where intervention within this pathway may be exploited for chemosensitization.

Keywords: Apoptosis; Chemoresistance; Lung Cancer; RIP; Reactive Oxygen Species (ROS).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Catalase / genetics
  • Catalase / metabolism*
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Gene Knockdown Techniques
  • Humans
  • Inhibitor of Apoptosis Proteins / biosynthesis*
  • Inhibitor of Apoptosis Proteins / genetics
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Reactive Oxygen Species / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • X-Linked Inhibitor of Apoptosis Protein / biosynthesis*
  • X-Linked Inhibitor of Apoptosis Protein / genetics


  • Antineoplastic Agents
  • Inhibitor of Apoptosis Proteins
  • MIRN146 microRNA, human
  • MicroRNAs
  • Reactive Oxygen Species
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Catalase
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Cisplatin