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abstract
We
have earlier demonstrated that breast cancer and small-cell lung cancer
express functional NMDA receptors that can be targeted to promote cancer
cell death. Human ovarian cancer tissues and human ovarian cancer cell
lines (SKOV3, A2008, and A2780) have now been shown to also express
NMDA-receptor subunit 1 (GluN1) and subunit 2B (GluN2B). Seventeen
ovarian cancers in two arrays were screened by immunohistochemistry
using polyclonal antibodies that recognize an extracellular moiety on
GluN1 and on GluN2B. These specimens comprised malignant tissue with
pathology diagnoses of serous papillary cystadenocarcinoma, endometrioid
adenocarcinoma, and clear-cell carcinoma. Additionally, archival
tissues defined as ovarian adenocarcinoma from ten patients treated at
this institute were also evaluated. All of the cancerous tissues
demonstrated positive staining patterns with the NMDA-receptor
antibodies, while no staining was found for tumor-adjacent normal
tissues or sections of normal ovarian tissue. Human ovarian
adenocarcinoma cell lines (A2008, A2780, SKOV3) were demonstrated to
express GluN1 by Western blotting, but displayed different levels of
expression. Through immunocytochemistry utilizing GluN1 antibodies and
imaging using a confocal microscope, we were able to demonstrate that
GluN1 protein is expressed on the surface of these cells. In addition to
these findings, GluN2B protein was demonstrated to be expressed using
polyclonal antibodies against this protein. Treatment of all ovarian
cell lines with antibodies against GluN1 was found to result in
decreased cell viability (P<0.001), with decreases to 10%-25%
that of untreated cells. Treatment of control HEK293 cells with various
dilutions of GluN1 antibodies had no effect on cell viability. The GluN1
antagonist MK-801 (dizocilpine maleate) and the GluN2B antagonist
ifenprodil, like antibodies, dramatically decreased the viability of
A2780 ovarian tumor cells (P<0.01). Treatment of A2780 tumor
xenografts with ifenprodil (2.5 mg/kg body weight/day) significantly
reduced tumor growth in nu/nu mice. Our findings suggest that both GluN1
and GluN2B proteins as membrane components could be readily available
targets for the treatment of most ovarian cancers.
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