title: Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies.
abstract: Targeted therapies using small-molecule inhibitors (SMIs) are commonly used in metastatic renal cell cancer (mRCC) patients; patients often develop drug resistance and eventually succumb to disease. Currently, understanding of mechanisms leading to SMIs resistance and any identifiable predictive marker(s) are still lacking. We discovered that DAB2IP, a novel Ras-GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. Loss of DAB2IP in RCC cells enhances their sensitivities to growth factor stimulation and resistances to SMI (such as mammalian target of rapamycin (mTOR) inhibitors). Mechanistically, loss of DAB2IP results in the activation of extracellular signal-regulated kinase/RSK1 and phosphoinositide-3 kinase/mTOR pathway, which synergizes the induction of hypoxia-inducible factor (HIF)-2α expression. Consequently, elevated HIF-2α suppresses p21/WAF1 expression that is associated with resistance to mTOR inhibitors. Thus combinatorial targeting both pathways resulted in a synergistic tumor inhibition. DAB2IP appears to be a new prognostic/predictive marker for mRCC patients, and its function provides a new insight into the molecular mechanisms of drug resistance to mTOR inhibitors, which also can be used to develop new strategies to overcome drug-resistant mRCC.
authors.affiliation: Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.|Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.
authors.forename: K
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: E-J
authors.initials: EJ
authors.lastname: Yun
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: R-C
authors.initials: RC
authors.lastname: Pong
authors.affiliation: Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Authement
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Hernandez
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Republic of China, Taiwan.
authors.forename: T-L
authors.initials: TL
authors.lastname: Cha
authors.affiliation: Department of Urology, China Medical University Hospital, Taichung, Republic of China, Taiwan.
authors.forename: H-C
authors.initials: HC
authors.lastname: Wu
authors.affiliation: Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Margulis
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lotan
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Brugarolas
authors.affiliation: Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.
authors.forename: D
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J-T
authors.initials: JT
authors.lastname: Hsieh
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D015398:Signal Transduction / Q000235:genetics; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D020703:ras GTPase-Activating Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C462952:DAB2IP protein, human; D047428:Protein Kinase Inhibitors; D020703:ras GTPase-Activating Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus