title: The role of p66shc in taxol- and dichloroacetic acid-dependent renal toxicity.
abstract: OBJECTIVE
  Taxol and dichloroacetic acid (DCA) are anticancer agents with potential renal toxicity. Previously, we have shown that the Ser36-phosphorylated p66shc adaptor protein mediates renal toxicity of selected anticancer modalities through increasing production of intracellular reactive oxygen species and consequent mitochondrial depolarization. Here, we analyzed whether p66shc plays a role in potential renal toxicity of Taxol and DCA.
  
  
  METHODS
  Cultured renal proximal tubule cells (TKPTS) were used. ROS production, mitochondrial depolarization (JC-1), cell injury [lactate dehydrogenase (LDH) release] and Ser36 phosphorylation of p66shc were determined after treatment with Taxol and DCA. Involvement of p66shc in adverse effects of these drugs was determined in p66shc knockdown, Ser36 phosphorylation (S36A) and cytochrome c-binding (W134F)- deficient cells.
  
  
  RESULTS
  Both Taxol and DCA increased ROS production, mitochondrial depolarization, injury and Ser36 phosphorylation of p66shc in TKPTS cells. We showed that ROS production is responsible for mitochondrial depolarization and consequent injury. Knockdown of p66shc, mutation of its Ser36 (S36A) or cytochrome c binding site (W134F) attenuated adverse effects of the two drugs.
  
  
  CONCLUSIONS
  Taxol and DCA are potentially nephrotoxic owing their adverse effects on activation of p66shc. Manipulation of expression or activity of p66shc may provide a means of ameliorating nephrotoxicity of these agents.
authors.affiliation: Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, USA. iarany@umc.edu
authors.forename: István
authors.initials: I
authors.lastname: Arany
authors.forename: Jeb S
authors.initials: JS
authors.lastname: Clark
authors.forename: Dustin
authors.initials: D
authors.lastname: Reed
authors.forename: István
authors.initials: I
authors.lastname: Szabó
authors.forename: István
authors.initials: I
authors.lastname: Ember
authors.forename: Luis A
authors.initials: LA
authors.lastname: Juncos
mesh_terms: D000818:Animals; D045304:Cytochromes c / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000009:adverse effects*; D055785:Gene Knockdown Techniques; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000009:adverse effects*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D010768:Phosphoserine; D045304:Cytochromes c; D003999:Dichloroacetic Acid; D017239:Paclitaxel
keywords: Taxol; dichloroacetic acid; p66shc; renal; toxicity