NMDA receptors are expressed by small-cell lung cancer and are potential targets for effective treatment

Abstract

We previously showed that functional N-methyl-D-aspartate (NMDA) receptors are expressed by human neuroblastoma cells. In this study we demonstrate functional NMDAR1 and NMDAR2 receptors are expressed by small-cell lung cancer (SCLC) classical cell lines NCI H146, NCI H345, and DMS 53, by variant cell line NCI H82, and by most SCLC tumors, and that these receptors are important for the growth of human SCLC tumor xenografts in mice. Reverse transcription-polymerase chain reaction demonstrated mRNA for both receptors, with sequences identical to those for human mRNAs, are expressed in all four cell lines, and these generated proteins of the expected sizes 120 and 170 kDa. Cell viability tests showed cell growth was significantly (P < 0.0001) impaired by NMDAR1 antagonists MK-801 and memantine. Ifenprodil and Ro25-6981, NMDAR2B antagonists at the polyamine site, also significantly (P < 0.001) inhibited the growth/survival of these cells. Alternatively, the glycine-binding antagonist, L701, 324, increased viability to 140% and 120% in NCI H345 and NCI H82 cells after 48 hours of incubation. Immunohistochemistry of SCLC tumors with our polyclonal antibodies gave specific positive staining for the NMDAR1 receptor in 8 of 10 tissues examined. Small amounts of these same antibodies significantly reduced the growth of NCI-H345 cells up to 25% (P < 0.001). When NCI H345 cells were grown as tumor xenografts in mice, the growth of these tumors was reduced by 60% (P < 0.001) by treatments with MK-801 over five days. All of these data point to active NMDAR receptors possibly having an important influence on SCLC growth and survival.

Memantine Induces NMDAR1-Mediated Autophagic Cell Death in Malignant Glioma Cells

“…Several studies reported that a glutamate receptor antagonist inhibits tumor growth, whereas a glutamate scavenger shows positive results in survival of animals with glioma21,22). NMDAR antagonists, such as memantine, MK-801 (dizocilpine), ifenprodil, Ro25-6981, and AP5, have an antiproliferative effect on cancer cells1,17,22,25,28). Our study also showed that memantine has an antiproliferative effect on human glioma cell lines.…”

“…In glioma cells, AMPAR is believed to promote cellular proliferation and survival, via activation of the PI3K/AKT pathway, EGFR expression and the MAPK pathway8,10,23). NMDAR antagonists also have the potential for inhibiting tumor proliferation1,17,22,25). Dizocilpine, an NMDAR1 antagonist, inhibits proliferation of lung cancer cell lines by inhibiting the extracellular signal-regulated kinase 1/2 pathway25).…”

“…Memantine has an antiproliferative effect on tumor cells1,17,22,25), but its effect on autophagy has yet to be elucidated. The aim of this study was to test whether memantine can cause autophagic cell death in glioma cells.…”

NMDA receptors on the surface of cancer cells: Target for chemotherapy?

“…This observation was replicated with another glycine B site antagonist (L-701,252) using the NCI-H345 cell line. The relevance of NMDAR1 receptors to tumor cell proliferation was further shown with affinity-purified polyclonal antibodies to NMDAR1, which were able to significantly reduce proliferation ( P < 0.001) at dilutions of 1:10 and 1:50 [4]. These data support the accessibility of the receptor protein on the cell surface.…”

“…Human small cell lung cancer (SCLC) tumor cell lines (i.e., NCI-H345, DMS-53, NCI-H146, and NCI-H82) were shown to express functional NMDA receptors; additionally, tissue sections of eight of 10 SCLC tumors stained positive with anti-NMDAR1 antibodies [4]. Moreover, all six of the sections of metastatic and recurrent disease stained strongly positive for expression of NMDAR1 .…”