title: Nuclear transportation of exogenous epidermal growth factor receptor and androgen receptor via extracellular vesicles.
abstract: Epidermal growth factor receptor (EGFR) plays a central role in the progression of several human malignancies. Although EGFR is a membrane receptor, it undergoes nuclear translocation, where it has a distinct signalling pathway. Herein, we report a novel mechanism by which cancer cells can directly transport EGFR to the nucleus of other cells via extracellular vesicles (EVs). The transported receptor is active and stimulates the nuclear EGFR pathways. Interestingly, the translocation of EGFR via EVs occurs independently of the nuclear localisation sequence that is required for nuclear translocation of endogenous EGFR. Also, we found that the mutant receptor EGFRvIII could be transported to the nucleus of other cells via EVs. To assess the role of EVs in the regulation of an actual nuclear receptor, we studied the regulation of androgen receptor (AR). We found that full-length AR and mutant variant ARv7 are secreted in EVs derived from prostate cancer cell lines and could be transported to the nucleus of AR-null cells. The EV-derived AR was able to bind the androgen-responsive promoter region of prostate specific antigen, and recruit RNA Pol II, an indication of active transcription. The nuclear-translocated AR via EVs enhanced the proliferation of acceptor cells in the absence of androgen. Finally, we provide evidence that nuclear localisation of AR could occur in vivo via orthotopically-injected EVs in male SCID mice prostate glands. To our knowledge, this is the first study showing the nuclear translocation of nuclear receptors via EVs, which significantly extends the role of EVs as paracrine transcriptional regulators.
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada.
authors.forename: Jolene
authors.initials: J
authors.lastname: Read
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada.
authors.forename: Alistair
authors.initials: A
authors.lastname: Ingram
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada.
authors.forename: Hassan A
authors.initials: HA
authors.lastname: Al Saleh
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada.
authors.forename: Khrystyna
authors.initials: K
authors.lastname: Platko
authors.affiliation: Medical School, University of Ottawa, Ottawa, Canada.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gabriel
authors.affiliation: Division of Urology, Department of Surgery, McMaster University, Canada.
authors.forename: Anil
authors.initials: A
authors.lastname: Kapoor
authors.affiliation: Division of Urology, Department of Surgery, McMaster University, Canada.
authors.forename: Jehonathan
authors.initials: J
authors.lastname: Pinthus
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada.
authors.forename: Fadwa
authors.initials: F
authors.lastname: Majeed
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
authors.forename: Talha
authors.initials: T
authors.lastname: Qureshi
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada. Electronic address: alnedaw@mcmaster.ca.
authors.forename: Khalid
authors.initials: K
authors.lastname: Al-Nedawi
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D000067128:Extracellular Vesicles / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D011944:Receptors, Androgen; D066246:ErbB Receptors
keywords: Androgen receptor; EGFR; Exosomes; Extracellular vesicles; Microvesicles; Nuclear receptors; Prostate cancer; Transcrition factors