title: Tyrosine receptor kinase B silencing inhibits anoikis‑resistance and improves anticancer efficiency of sorafenib in human renal cancer cells.
abstract: Renal cell carcinoma (RCC) is the most common solid neoplasm of adult kidney, and the major treatment for metastatic RCC (mRCC) is molecular targeted therapy. Sorafenib, as a multi-targeted tyrosine kinase inhibitor (TKI), has significantly improved clinical outcomes of mRCC patients. However, complete or long-term remissions are rarely achieved due to intolerance to dose-related adverse effects. It is therefore, necessary to explore novel target molecules for treatment or to enhance the therapeutic efficiency of present TKI for mRCC treatment. Anoikis is a specific type of apoptosis that plays a vital physiological role in regulating tissue homoeostasis. Anoikis-resistance is of critical importance for metastasis of various human cancers including mRCC. However, the precise mechanisms on anoikis-resistance in mRCC are still unclear. Tyrosine receptor kinase B (TrkB) belongs to the Trk family of neurotrophin receptors. Previous investigations have implied that activation or overexpression of TrkB promoted proliferation, survival, angiogenesis, anoikis-resistance and metastasis in human cancers. Yet, the correlation between TrkB and anoikis-resistance in mRCC has rarely been reported. The aim of the present study was to explore the impact of TrkB on anoikis-resistance and targeted therapy in mRCC. Our data revealed that anoikis-resistant ACHN cells presented with tolerance to detachment-induced apoptosis, excessive proliferation and aggressive invasion, accompanied by upregulation of TrkB expression in contrast to parental cells. Furthermore, TrkB silencing caused apoptosis, inhibited proliferation, retarded invasion as well as improved anticancer efficiency of sorafenib in anoikis-resistant ACHN cells through inactivation of PI3K/Akt and MEK/ERK pathways. Our data may offer a novel potential therapeutic strategy for mRCC.
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Urology, Haikou People's Hospital/Haikou Hospital Affiliated to Xiangya School of Medicine, Central South University, Haikou, Hainan 570208, P.R. China.
authors.forename: Zengshu
authors.initials: Z
authors.lastname: Xing
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Xuechao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Yarong
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Xing
mesh_terms: D023102:Anoikis / Q000187:drug effects / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D020813:Receptor, trkB; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib
chemical_list: D008562:Membrane Glycoproteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human