title: Adrenomedullin blockade suppresses sunitinib-resistant renal cell carcinoma growth by targeting the ERK/MAPK pathway.
abstract: To evaluate the mechanisms underlying sunitinib resistance in RCC and to identify targets that may be used to overcome this resistance.
  
  
  
  Reanalysis of transcriptome microarray datasets (GSE64052 and GSE76068) showed that adrenomedullin expression was increased in sunitinib-resistant tumors. And adrenomedullin expression was increased in sunitinib-resistant tumor xenografts, accompanied by upregulation of phospho-ERK levels. However, blocking adrenomedullin inhibited sunitinib-resistant tumor growth. Treatment of RCC cells with sunitinib and ADM22-52 was superior to monotherapy with either agent. Additionally, adrenomedullin upregulated cAMP and activated the ERK/MAPK pathway, promoting cell proliferation, while knockdown of adrenomedullin inhibited RCC cell growth and invasion in vitro.
  
  
  
  We searched the Gene Expression Omnibus (GEO) database to find data regarding sunitinib-resistant RCC. These data were subsequently reanalyzed to identify targets that contribute to sunitinib resistance, and adrenomedullin upregulation was found to mediate sunitinib resistance in RCC. Then, we created an RCC mouse xenograft model. Mice were treated with sunitinib, an adrenomedullin receptor antagonist (ADM22-52), a MEK inhibitor (PD98059) and different combinations of these three drugs to investigate their effects on tumor growth. RCC cells (786-0) were cultured in vitro and treated with an ADM22-52 or PD98059 to determine whether adrenomedullin activates the ERK/MAPK pathway. Adrenomedullin was knocked down in 786-0 cells via siRNA, and the effects of this knockdown on cell were subsequently investigated.
  
  
  
  Adrenomedullin plays an important role in RCC resistance to sunitinib treatment. The combination of sunitinib and an adrenomedullin receptor antagonist may result in better outcomes in advanced RCC patients.
authors.affiliation: Department of Interventional Radiology, Tangshan Gongren Hospital, Hebei Medical University, Tangshan 063000, P.R. China.
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, 10029, USA.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Urologic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
authors.forename: Na
authors.initials: N
authors.lastname: Qiao
authors.affiliation: Department of Urologic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Urologic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Urologic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Urologic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Urologic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Urologic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
authors.forename: Changbao
authors.initials: C
authors.lastname: Qu
authors.affiliation: Department of Urologic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Urologic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
authors.forename: Dongbin
authors.initials: D
authors.lastname: Wang
mesh_terms: D053607:Adrenomedullin / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011379:Prognosis; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D053607:Adrenomedullin; D048049:Extracellular Signal-Regulated MAP Kinases; D000077210:Sunitinib
keywords: ERK; adrenomedullin; renal cell carcinoma; tyrosine kinase inhibitor