title: NMDA receptors on the surface of cancer cells: target for chemotherapy?
abstract: The mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a therapeutic target for many types of cancers. NMDA receptors regulate mTOR signalling activity; their inappropriate expression on several human cancer cell lines represents a potential therapeutic avenue to control dysregulated growth, division and invasiveness. Targeting these receptors with selective ligands (e.g., glycineB site ligands) may be a less toxic and more tolerable approach than administering compounds acting at the mTORC1 complex itself, such as rapamycin and its derivatives. Thus, testing glycineB site ligands in relevant in vitro and in vivo paradigms with established human cancer cells that express NMDA receptors on their surface could provide proofs of concept/principle that would encourage exploration of these and other "non-toxic" strategies. Interestingly, in some cancer models that express NMDA receptors on their surface, NMDA receptor antagonists, such as MK-801 (dizocilpine), were shown to possess anti-proliferative and anti-invasive effects, which conflict with hypotheses about promoting NMDA receptor activation as a cancer chemotherapeutic strategy. Whether NMDA receptor activation or antagonism is associated with anti-proliferative and anti-invasive effects may reflect differences between cancer cell lines in terms of the proteins associated with the NMDA receptors on their cell surfaces, which, in turn, could lead to different "downstream" effects on cascades of intracellular phosphorylations. Irrespective of whether activation or antagonism is associated with anti-proliferative and anti-invasive effects for specific types of cancer, data are emerging that support exploration of targeting NMDA receptors expressed on the surface of cancer cells as a therapeutic strategy.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA, United States. Electronic address: deutscsi@evms.edu.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Deutsch
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States.
authors.forename: Amy H
authors.initials: AH
authors.lastname: Tang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA, United States.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Burket
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Benson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Cancer; Chemotherapy; NMDA receptor; mTOR
references.citation: Histochem Cell Biol. 2009 Oct;132(4):435-45
references.pmid: 19526364
references.citation: Int J Cancer. 2007 Nov 1;121(9):1994-2000
references.pmid: 17620329
references.citation: Front Neuroanat. 2011 Jul 29;5:47
references.pmid: 21863137
references.citation: Nat Neurosci. 2003 Jan;6(1):34-42
references.pmid: 12483215
references.citation: Psychopharmacology (Berl). 2005 Apr;179(1):30-53
references.pmid: 15761697
references.citation: Oncology. 2013;84(1):43-56
references.pmid: 23128843
references.citation: Trends Pharmacol Sci. 2011 Dec;32(12):726-33
references.pmid: 21996280
references.citation: Cancer Res. 2006 Apr 1;66(7):3409-18
references.pmid: 16585162
references.citation: J Membr Biol. 2005 Jun;205(3):125-8
references.pmid: 16362500
references.citation: Clin Pharmacol. 2010;2:31-40
references.pmid: 22291485
references.citation: Br J Cancer. 2006 Jan 30;94(2):195-9
references.pmid: 16404421
references.citation: J Cell Physiol. 2004 Aug;200(2):309-17
references.pmid: 15174101
references.citation: Proc Natl Acad Sci U S A. 2001 May 22;98(11):6372-7
references.pmid: 11331750
references.citation: J Oral Pathol Med. 2004 Oct;33(9):533-7
references.pmid: 15357673
references.citation: Physiol Genomics. 2001 Feb 07;5(1):21-33
references.pmid: 11161003
references.citation: Breast Cancer Res Treat. 2010 Jul;122(2):307-14
references.pmid: 19784770
references.citation: J Biol Chem. 2012 Feb 10;287(7):4411-8
references.pmid: 22147701
references.citation: J Neurosci. 2007 Jan 17;27(3):449-58
references.pmid: 17234578
references.citation: Steroids. 2011 Dec 11;76(13):1409-18
references.pmid: 21925193
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15605-10
references.pmid: 16230611
references.citation: BMC Cancer. 2011 Jun 05;11:220
references.pmid: 21639937