title: LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma.
abstract: BACKGROUND
  Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs.
  
  
  METHODS
  We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib.
  
  
  RESULTS
  The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet.
  
  
  CONCLUSIONS
  The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Sei
authors.initials: S
authors.lastname: Naito
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Makhov
authors.affiliation: Department of Hematology/Oncology, Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Astsaturov
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Golovine
authors.affiliation: Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Tulin
authors.affiliation: Division of Urologic Oncology, Department of Surgery, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kutikov
authors.affiliation: Division of Urologic Oncology, Department of Surgery, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Uzzo
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Kolenko
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000008:administration & dosage / Q000378:metabolism; D004347:Drug Interactions / Q000208:ethnology / Q000235:genetics*; D053492:Elafin / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011758:Pyrroles / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: D008078:Cholesterol, LDL; D053492:Elafin; D007211:Indoles; C506806:PI3 protein, human; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D002784:Cholesterol; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000077210:Sunitinib