title: Differential expression of organic cation transporter OCT-3 in oral premalignant and malignant lesions: potential implications in the antineoplastic effects of metformin.
abstract: BACKGROUND
  Recent evidence indicates that metformin, a biguanide used as first-line treatment for type 2 diabetes, prevents the conversion of carcinogen-induced oral dysplasias into head and neck squamous cell carcinomas (HNSCC), most likely by inhibiting mammalian target of rapamycin complex 1 (mTORC1) oncogenic signaling. Whether metformin acts directly at the primary tumor site or indirectly by modulating hormonal secretion from extratumoral organs remains unknown. As organic cation transporters (OCT) belonging to the solute carrier 22A gene family, including OCT-1, OCT-2, and OCT-3, mediate metformin uptake and activity, it is critical to define what role they play in the antineoplastic activity of metformin.
  
  
  METHODS
  Immunohistochemical and immunoblotting techniques were used in normal, dysplastic and HNSCC tissues, and HNSCC cell lines, respectively, to determine OCTs expression levels.
  
  
  RESULTS
  We report that only OCT-3 was highly expressed in a number of HNSCC cell lines, oral epithelial dysplasias, and well to moderately differentiated HNSCC. Indeed, inhibition of OCT-3 expression and activity in HNSCC cells prevented metformin-induced AMP-activated protein kinase activation and mTORC1 pathway inhibition. Moreover, in oral dysplasias, high OCT-3 expression localized to epithelial compartments where mTORC1 signaling was also upregulated suggestive of a potential local effect of metformin.
  
  
  CONCLUSIONS
  The concept of using metformin as a chemopreventive agent to control head and neck carcinogenesis is promising. Further work is warranted to elucidate largely unexplored mechanisms of metformin uptake and pharmacologic action that may ultimately influence the selection of the most suitable patients who can benefit from metformin in head and neck cancer chemoprevention.
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, MD, USA.
authors.forename: Harsh
authors.initials: H
authors.lastname: Patel
authors.forename: Rania H
authors.initials: RH
authors.lastname: Younis
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ord
authors.forename: John R
authors.initials: JR
authors.lastname: Basile
authors.forename: Abraham
authors.initials: A
authors.lastname: Schneider
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D003345:Corticosterone / Q000494:pharmacology; D003593:Cytoplasm / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects; D004848:Epithelium / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology*; D009062:Mouth Neoplasms / Q000473:pathology*; D046912:Multiprotein Complexes; D027701:Organic Cation Transport Proteins / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000187:drug effects; D011230:Precancerous Conditions / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects; D015854:Up-Regulation; D000099254:Organic Cation Transporter 3
chemical_list: D055372:AMP-Activated Protein Kinases; D016588:Anticarcinogenic Agents; D003345:Corticosterone; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin; D046912:Multiprotein Complexes; D027701:Organic Cation Transport Proteins; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D000099254:Organic Cation Transporter 3