title: NGAL can alternately mediate sunitinib resistance in renal cell carcinoma.
abstract: OBJECTIVE
  Serum NGAL is highly expressed in patients with advanced renal cancer treated with sunitinib. We investigated the role of NGAL in sunitinib resistance in renal cell carcinoma to identify potential tactics to overcome it.
  
  
  METHODS
  NGAL expression was correlated with sunitinib sensitivity. Vascular endothelial growth factor related upstream Ras, Erk1/2 and STAT1 phosphorylation activity in Caki-1 and NGAL transfected Caki-1 cells after sunitinib treatment was analyzed using Western blot. NGAL and vascular endothelial growth factor-A interaction with sunitinib therapeutic efficacy was monitored in renal cell carcinoma tumor xenografted mice by tumor growth inhibition, serum NGAL and vascular endothelial growth factor-a levels, and microscopic examination of tumor microvascular density.
  
  
  RESULTS
  Sunitinib cytotoxicity in various renal cell carcinoma cell lines was reversibly related to NGAL expression. Sunitinib showed the lowest 50% inhibitory concentration (5.53 μM) in Caki-1 cells, which had the lowest NGAL expression of these renal cell carcinoma cell lines. After sunitinib treatment adding NGAL inhibited Ras and Erk1/2 phosphorylation but activated STAT1α phosphorylation in Caki-1 cells and Caki-1 cells transfected with NGAL. In a xenograft mouse model sunitinib significantly inhibited tumor growth in Caki-1 mice. NGAL transfected Caki-1 mice had higher serum NGAL and lower vascular endothelial growth factor-A than Caki-1 mice. Microvascular density was decreased in Caki-1 mice with sunitinib treatment.
  
  
  CONCLUSIONS
  NGAL in tumor cells may show crosstalk with vascular endothelial growth factor-a and alternative activation in stimulating tumor growth during sunitinib treatment. It may become a therapeutic target to reverse sunitinib resistance in renal cell carcinoma.
authors.affiliation: Uro-Oncology Laboratory, Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Tainan, Taiwan, Republic of China. Electronic address: yuds@ms21.hinet.net.
authors.forename: Dah-Shyong
authors.initials: DS
authors.lastname: Yu
authors.affiliation: Graduate Institute of Life Science, National Defense Medical Center, Tainan, Taiwan, Republic of China.
authors.forename: Chia-Lun
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Uro-Oncology Laboratory, Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Tainan, Taiwan, Republic of China.
authors.forename: Szu-Yuan
authors.initials: SY
authors.lastname: Ping
authors.affiliation: Uro-Oncology Laboratory, Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Tainan, Taiwan, Republic of China.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Huang
authors.affiliation: Division of Urology, Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan, Republic of China; Department of Optometry, Chung Hwa University of Medical Technology, Tainan, Taiwan, Republic of China. Electronic address: cmh7530@mail.chimei.org.tw.
authors.forename: Kun-Hung
authors.initials: KH
authors.lastname: Shen
mesh_terms: D000209:Acute-Phase Proteins / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000502:physiology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D000209:Acute-Phase Proteins; D000970:Antineoplastic Agents; D007211:Indoles; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000077210:Sunitinib
keywords: LCN2 protein; carcinoma; drug resistance; human; kidney; renal cell; sunitinib