Somatostatin analogues inhibit cancer cell proliferation in an SSTR2-dependent manner via both cytostatic and cytotoxic pathways

Somatostatin receptors (SSTRs) are inhibitory G-protein coupled receptors that are ubiquitously expressed in normal and cancer cells. Somatostatins (SST) are the natural ligands for SSTRs and act as inhibitory regulators of hormone secretion and proliferation. Octreotide and RC-160 (vapreotide) are two well tolerated SSTR2/SSTR5 selective somatostatin analogues (SSA) that have been used in the treatment of cancers with mixed outcomes. Loss-of-expression of SSTR2 in tumor tissues has been suggested to correlate to tumor progressions and to the poor outcomes of somatostatin analogue treatment in certain clinical trials. In this study, exogenous human SSTR2 was overexpressed in two cancer cell lines, capan-2 cells and A549 cells, which had different profiles of endogenous SSTR expression. It was shown that overexpression of SSTR2 dramatically inhibited the proliferation of SSTR2-positive and SSTR2-negative cancer cells. Further growth inhibition of these cancer cells overexpressing SSTR2 was observed by application of octreotide/RC-160 in a dose-dependent fashion. In addition, immunoassay demonstrated that SSA/SSTR2 inhibited proliferation via both cell cycle arresting and promoting apoptosis. The results suggested that SSTR2 could be a promising candidate for gene therapy for SSTR2-positive and SSTR2-negative tumors. The cellular level of SSTR2 might be a critical factor that could affect both tumor progression and the outcomes of somatostatin analogue treatment.