Stubbs, M.; Khan, K.; Savage, K.; McStay, M.; Dhillon, A.P.; Caplin, M.E.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA29
Academic Journal
Aim: To investigate the role of gastrin and the CCK2 gastrin receptor in the proliferation of neuroendocrine tumour cell lines. Methods: CRI-G1, NCI-H727, RIN 5F, and SHP 77 neuroendocrine tumour cells were studied. CCK2 receptor was detected in cell lysates by immunoblotting using an antibody (antiGRE1) raised against the C-terminal sequence of the receptor. For uptake studies, cells were cultured in chamber well slides. The cells were incubated with either gastrin 7 coupled to rhodol green dye or antiGRE1 labelled with Alexa Fluor 546 dye for 1 h at 37°C. After fixation, cells were viewed under a fluorescence microscope. Cells exposed to the antiGRE1 antibody were subsequently counterstained for apoptosis using the TUNEL method (ApopTag FITC kit). Proliferation studies were performed by incubating cells alone or with CCK2 antagonist PD 135 at 10-4 M for 96 h followed by measurement of cell number using the MTT assay. Results: Immunoreactivity to CCK2 was detected in all cell lines. A 122kD band was seen at in all 4 cell lines with an additional 186 kD band seen only in the CRI G1 and RIN 5F celIs. Uptake of rhodol green labelled gastrin 7 and of Alexa Fluor 546 labelled antiGRE1 antibody was seen in all 4 cell lines with the fluorescence being most prominent in the SHP 77 cells. ApopTag FITC staining revealed a coincidence of antibody uptake and apoptosis in the latter cell line. PD135 at a concentration of 10-4 M gave inhibition of proliferation in all 4 cell lines (27-92% reduction compared to controls). Conclusions: We present evidence for the existence of CCK2 receptor in NET cell lines. We have demonstrated uptake of gastrin peptide and antibody by tumour cells and a ro]e for CCK2 in proliferation. These results suggests that the gastrin pathway could be a potential target for treatment in neuroendocrine tumours.


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