title: EGFR-SGLT1 interaction does not respond to EGFR modulators, but inhibition of SGLT1 sensitizes prostate cancer cells to EGFR tyrosine kinase inhibitors.
abstract: BACKGROUND
  Overexpression of epidermal growth factor receptor (EGFR) is associated with poor prognosis in malignant tumors. Sodium/glucose co-transporter 1 (SGLT1) is an active glucose transporter that is overexpressed in many cancers including prostate cancer. Previously, we found that EGFR interacts with and stabilizes SGLT1 in cancer cells.
  
  
  METHODS
  In this study, we determined the micro-domain of EGFR that is required for its interaction with SGLT1 and the effects of activation/inactivation of EGFR on EGFR-SGLT1 interaction, measured the expression of EGFR and SGLT1 in prostate cancer tissues, and tested the effect of inhibition of SGLT1 on the sensitivity of prostate cancer cells to EGFR tyrosine inhibitors.
  
  
  RESULTS
  We found that the autophosphorylation region (978-1210 amino acids) of EGFR was required for its sufficient interaction with SGLT1 and that this interaction was independent of EGFR's tyrosine kinase activity. Most importantly, the EGFR-SGLT1 interaction does not respond to EGFR tyrosine kinase modulators (EGF and tyrosine kinase inhibitors). EGFR and SGLT1 co-localized in prostate cancer tissues, and inhibition of SGLT1 by a SGLT1 inhibitor (Phlorizin) sensitized prostate cancer cells to EGFR inhibitors (Gefitinib and Erlotinib).
  
  
  CONCLUSIONS
  These data suggest that EGFR in cancer cells can exist as either a tyrosine kinase modulator responsive status or an irresponsive status. SGLT1 is a protein involved in EGFR's functions that are irresponsive to EGFR tyrosine kinase inhibitors and, therefore, the EGFR-SGLT1 interaction might be a novel target for prostate cancer therapy.
authors.affiliation: Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, Texas 77204-5001, USA.
authors.forename: Jiangong
authors.initials: J
authors.lastname: Ren
authors.forename: Lakshmi R
authors.initials: LR
authors.lastname: Bollu
authors.forename: Fei
authors.initials: F
authors.lastname: Su
authors.forename: Guang
authors.initials: G
authors.lastname: Gao
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Huang
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Zhang
authors.initials: Z
authors.lastname: Weihua
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; D011799:Quinazolines; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C489254:AEE 788; D000077156:Gefitinib
keywords: EGFR; SGLT1; cancer; glucose; prostate