Human somatostatin receptor mediated antiproliferative action evokes subtype selective cytotoxic and cytostatic signaling.

Somatostatin (SST)b exerts diverse biological actions through a family of five cell surface SST receptors (SSTR) subtypes. These can be categorized into two subgroups, one consisting of SSTRs 2,3 and 5 and the other made up of SSTRs 1 and 4 on the basis of their ability or inability to bind octaand hexapeptide SST analogs [1, 2]. SST influences multiple second messenger systems including adenylyl cyclase-cAMP, Ca2+, K+, protein tyrosine phosphatase (PTP), protein serine phosphatase, mitogen activated protein kinase and Na+/H+ antiporter, and exerts an inhibitory effect on hormone secretion, cell growth and proliferation (reviewed in [1-3]). SST-induced inhibition of cell proliferation can elicit either cytostatic (growth arrest) as well as cytotoxic (apoptosis) in tumor cells which express multiple SSTR subtypes [4-9]. We have shown that SSTR mediated cytotoxic signaling in MCF-7 breast cancer cells involves rapid recruitment of the src homology 2 domain containing tyrosine phosphatase SHP-1, is associated with the induction of the wild type (wt) tumor suppressor protein p53, the proapoptotic protein Bax and a cationinsensitive acidic endonuclease [9, 10]. The mechanism underlying its cytostatic signaling reported to occur in other tumor cells such as GH3 cells has not been elucidated. Molecular mediators that regulate cytotoxic and cytostatic events include the tumor suppressor protein p53, the cyclin dependent kinase inhibitor p2lWAFl/CIPl, the retinoblastoma protein pRB and the protooncogene product c-Myc. p53 can induce GI cell cycle arrest via p2lWAFl/CIPI in the presence of growth factors or trigger apoptosis by inducing Bax in the absence of mitogenic signals [11-13]. Both these actions of p53 are dependent on its ability to acquire wt conformation in a manner requiring dephosphorylation of phosphoserine residues [14]. c-Myc, like p53, can also induce either G1 arrest or apoptosis and moreover, can abrogate p2lwAFl/cIPl induced G1 arrest [15]. pRB in its hypophosphorylated form induces G, cell cycle arrest independent of p53 [16]. In order to determine if SST influences these mediators in a SSTR subtype selective manner to differentially regulate cell cycle progression and apoptosis we set out to elucidate human (h) SSTR subtype selectivity for cytotoxic and cytostatic signaling and demonstrated that SST-induced apoptosis is signaled uniquely via hSSTR3 whereas the other hSSTR subtypes signal G, cell cycle arrest without inducing apoptosis [17, 18]. Here I summarize current evidence demonstrating that SST elicits cytotoxic action uniquely via hSSTR3 in a p53 dependent manner whereas its cytostatic action is exerted through other subtypes involving induction of pRB in a p53-independent manner. We first assessed the subtype selectivity for regulating cell cycle in CHO-Ki cells stably expressing individual hSSTRs. Cells were treated with 100 nM OCT (hSSTRs 2,3,5)