Implications of apurinic/apyrimidinic endonuclease in reactive oxygen signaling response after cisplatin treatment of dorsal root ganglion neurons

Yanlin Jiang, Chunlu Guo, Michael Vasko, Mark Kelley

Research output: Contribution to journalArticle

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Abstract

Peripheral neuropathy is one of the major side effects of the anticancer drug cisplatin. Although previous work suggests that this neuropathy correlates with formation of DNA adducts in sensory neurons, growing evidence suggests that cisplatin also increases the generation of reactive oxygen species (ROS), which could cause DNA damage. Apurinic/apyrimidinic endonuclease/redox factor-1 (Ape1/Ref-1) is a multifunctional protein involved in DNA base excision repair of oxidative DNA damage and in redox regulation of a number of transcription factors. Therefore, we asked whether altering Ape1 functions would influence cisplatin-induced neurotoxicity. Sensory neurons in culture were exposed to cisplatin for 24 hours and several end points of toxicity were measured, including production of ROS, cell death, apoptosis, and release of the immunoreactive calcitonin gene-related peptide (iCGRP). Reducing expression of Ape1 in neuronal cultures using small interfering RNA (siRNA) enhances cisplatin-induced cell killing, apoptosis, ROS generation, and cisplatin-induced reduction in iCGRP release. Overexpressing wild-type Ape1 attenuates all the toxic effects of cisplatin in cells containing normal endogenous levels of Ape1 and in cells with reduced Ape1 levels after Ape1siRNA treatment. Overexpressing the redox deficient/repair competent C65-Ape1 provides partial rescue, whereas the repair-deficient Ape1 (N226A + R177A) does not protect neurons from cisplatin toxicity. We also observe an increase in phosphorylation of p53 after a decrease in Ape1 levels in sensory neuronal cultures. These results strongly support the notion that Ape1 is a potential translational target such that protecting Ape1 levels and particularly its DNA repair function could reduce peripheral neuropathy in patients undergoing cisplatin treatment.

Original languageEnglish
Pages (from-to)6425-6434
Number of pages10
JournalCancer Research
Volume68
Issue number15
DOIs
StatePublished - Aug 1 2008

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DNA-(Apurinic or Apyrimidinic Site) Lyase
Spinal Ganglia
Cisplatin
Oxygen
Neurons
Oxidation-Reduction
Reactive Oxygen Species
Calcitonin Gene-Related Peptide
Peripheral Nervous System Diseases
Sensory Receptor Cells
DNA Repair
DNA Damage
Apoptosis
DNA Adducts
Poisons
Drug-Related Side Effects and Adverse Reactions
Small Interfering RNA
Cell Death
Transcription Factors
Phosphorylation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Implications of apurinic/apyrimidinic endonuclease in reactive oxygen signaling response after cisplatin treatment of dorsal root ganglion neurons. / Jiang, Yanlin; Guo, Chunlu; Vasko, Michael; Kelley, Mark.

In: Cancer Research, Vol. 68, No. 15, 01.08.2008, p. 6425-6434.

Research output: Contribution to journalArticle

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