S100P Promotes Pancreatic Cancer Growth, Survival, and Invasion

Abstract

Purpose: In the current study, we examined the functional significance and mechanism of action of S100P in pancreatic cancer cells. Experimental Design: S100P levels were increased in Panc-1 cells, which do not express S100P, by transfection with an S100P cDNA and S100P levels were reduced in BxPC3 cells, which express high levels of S100P, by small interfering RNA gene silencing. Effects of these manipulations on cell proliferation, resistance to apoptotic insults, cell migration, and invasion were estimated in vitro using standard assays. The influences of S100P on tumor growth in vivo were studied using xenograft mouse models. To identify the mechanisms involved in these responses, coimmunoprecipitation studies were conducted with S100P with receptor for advanced glycation end products (RAGE) and the effects of inhibiting RAGE using an antagonistic peptide were analyzed. Results: S100P levels correlated with the rates of cell proliferation, survival, migration, and invasion in both cell models in vitro. In vivo, increased S100P levels increased the growth of tumors in mice with s.c.-implanted Panc-1 cells and decreased S100P levels decreased tumor growth after orthotopic implantation of BxPC-3 cells. A direct interaction between S100P and RAGE was indicated by coimmunoprecipitation of these molecules from pancreatic cancer cells. A RAGE antagonist peptide inhibited this interaction and also inhibited the biological effects of S100P on these cells in vitro. Conclusions: These data suggest that S100P plays a major role in the aggressiveness of pancreatic cancer that is likely mediated by its ability to activate RAGE. Thus, interference with S100P may provide a novel approach for treatment of pancreatic cancer.

Targeted disruption of S100P suppresses tumor cell growth by down-regulation of cyclin D1 and CDK2 in human hepatocellular carcinoma

“…However, despite the accumulating evidence supporting aberrant cell cycle regulation and tumorigenic potential of S100P, in many solid tumors, there is no information on its role in human HCC. Much of the experimental data have been obtained by S100P-transfected cells in vitro and in vivo as well as from DNA micrarray studies (14,15,(31)(32)(33). We have noted that S100P expression has been shown to gradually increase from dysplasia, precancerous lesions, to HCC based on our previous findings, which suggests large-scale molecular changes from the dysplastic nodule to HCC by expression profiling (34).…”

“…This protein was first purified from the placenta (12), and has been associated with a large number of diseases by both intracellular and extracellular mechanisms (14). In addition, the S100P protein has been recently considered a potential biomarker of cancer due to its frequent expression in different types of tumor tissues (15,30).…”

“…The primary function of S100P is to mediate the Ca 2+ -dependent signal transduction cascades involved in cell growth and differentiation, cell cycle regulation and metabolic control (8,10). Many studies have shown that S100P plays a role in carcinogenesis (14)(15)(16), and its expression has been shown to increase in several malignancies including those of the colon (17), breast (18), pancreas (19), prostate (20) and lung (21). In pancreatic cancer, S100P is over-expressed due INTERNATIONAL JOURNAL OF ONCOLOGY 35: 1257-1264, 2009 Targeted disruption of S100P suppresses tumor cell growth by down-regulation of cyclin D1 and CDK2 in human hepatocellular carcinoma to hypomethylation of specific genes (22).…”

Epigenetic deregulation of multiple S100 gene family members by differential hypomethylation and hypermethylation events in medulloblastoma

“…Overexpression of several of the S100 proteins is thought to be involved in tumour progression, such as S100A4, which is upregulated in many cancers including medulloblastoma and promotes angiogenesis and metastasis (Hernan et al, 2003;Emberley et al, 2004;Helfman et al, 2005;Garrett et al, 2006) and S100P which is associated with metastasis in breast and pancreatic cancer (Arumugam et al, 2005;Wang et al, 2006). Other S100 proteins are downregulated in tumours and have putative tumour suppressor roles, including S100A2 and S100A6 in prostate cancer (Rehman et al, 2005).…”

S100P, a potential novel prognostic marker in colorectal cancer

“…S100P could promote the proliferation, migration, and invasion of pancreatic cancer cell via a receptor for activated glycation end products (28), it also stimulated colon cancer cell proliferation and migration in vitro (20,21), and lung cancer cells in an autocrine manner (26,29). These findings may, at least partially, provide molecular insight into the relationship of S100P and prognosis in cancers.…”