title: The receptor tyrosine kinase Axl is an essential regulator of prostate cancer proliferation and tumor growth and represents a new therapeutic target.
abstract: Deregulation of the receptor tyrosine kinase Axl has been implicated in the progression of several human cancers. However, the role of Axl in prostate cancer remains poorly understood, and the therapeutic efficacy of Axl targeting remains untested. In this report we identified Axl as a new therapeutic target for prostate cancer. Axl is consistently overexpressed in prostate cancer cell lines and human prostate tumors. Interestingly, the blockage of Axl gene expression strongly inhibits proliferation, migration, invasion and tumor growth. Furthermore, inhibition of Axl expression by small interfering RNA regulates a transcriptional program of genes involved in cell survival, strikingly all connected to the nuclear factor-κB pathway. Additionally, blockage of Axl expression leads to inhibition of Akt, IKKα and IκBα phosphorylation, increasing IκBα expression and stability. Furthermore, induction of Akt phosphorylation by insulin-like growth factor 1 in Axl knockdown cells restores Akt activity and proliferation. Taken together, our results establish an unambiguous role for Axl in prostate cancer tumorigenesis with implications for prostate cancer treatment.
authors.affiliation: International Center for Genetic Engineering and Biotechnology, Cancer Genomics Group, Cape Town, South Africa.
authors.forename: J D
authors.initials: JD
authors.lastname: Paccez
authors.forename: G J
authors.initials: GJ
authors.lastname: Vasques
authors.forename: R G
authors.initials: RG
authors.lastname: Correa
authors.forename: J F
authors.initials: JF
authors.lastname: Vasconcellos
authors.forename: K
authors.initials: K
authors.lastname: Duncan
authors.forename: X
authors.initials: X
authors.lastname: Gu
authors.forename: M
authors.initials: M
authors.lastname: Bhasin
authors.forename: T A
authors.initials: TA
authors.lastname: Libermann
authors.forename: L F
authors.initials: LF
authors.lastname: Zerbini
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction; D015854:Up-Regulation; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human