Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury

Cancer Res. 2021 Feb 1;81(3):713-723. doi: 10.1158/0008-5472.CAN-20-1010. Epub 2020 Dec 7.


Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease. SIGNIFICANCE: These results reveal and highlight an unexpected role of APE2 via its interaction with MYH9 and suggest that APE2 has the potential to prevent acute kidney injury in patients with cisplatin-treated cancer. GRAPHICAL ABSTRACT:

Publication types

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

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / prevention & control
  • Animals
  • Antineoplastic Agents / adverse effects*
  • Carboplatin / adverse effects
  • Cisplatin / adverse effects*
  • DNA Damage
  • DNA, Mitochondrial / drug effects
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / drug effects
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / genetics
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism*
  • Endonucleases / drug effects
  • Endonucleases / genetics
  • Endonucleases / metabolism*
  • Hearing Loss, Sensorineural / chemically induced
  • Humans
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Diseases / genetics
  • Multifunctional Enzymes / drug effects
  • Multifunctional Enzymes / genetics
  • Multifunctional Enzymes / metabolism*
  • Mutation
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism*
  • Nephritis / chemically induced
  • Oxaliplatin / adverse effects
  • Phenotype
  • Thrombocytopenia / chemically induced
  • Up-Regulation / drug effects


  • Antineoplastic Agents
  • DNA, Mitochondrial
  • MYH9 protein, human
  • Multifunctional Enzymes
  • Myh9 protein, mouse
  • Oxaliplatin
  • Carboplatin
  • Apex2 protein, mouse
  • Endonucleases
  • Myosin Heavy Chains
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • Cisplatin

Supplementary concepts

  • Macrothrombocytopenia progressive deafness