The Role of S100P in the Invasion of Pancreatic Cancer Cells Is Mediated through Cytoskeletal Changes and Regulation of Cathepsin D

Abstract

Up-regulation of S100P, a member of the S100 calcium-binding protein family, is an early molecular event in the development of pancreatic cancer and it is expressed at high levels in both precursor lesions and invasive cancer. To gain more insight into the molecular mechanisms underlying the functional roles of this protein, we stably overexpressed S100P in the Panc1 pancreatic cancer cell line and identified the consequent changes in global protein expression by twodimensional difference in-gel electrophoresis. The observed changes in target proteins were confirmed by Western blot analysis and immunofluorescence, whereas their functional effect was investigated using motility and invasion assays. In this study, we have shown that overexpression of S100P led to changes in the expression levels of several cytoskeletal proteins, including cytokeratins 8, 18, and 19. We have also shown disorganization of the actin cytoskeleton network and changes in the phosphorylation status of the actin regulatory protein cofilin. Additionally, we have shown that overexpression of S100P leads to increased expression of another early pancreatic cancer marker, S100A6, as well as the aspartic protease cathepsin D, both of which are involved in cellular invasion. Functional studies showed that the increased invasive potential of S100P-overexpressing cells was at least partially due to the increase in cathepsin D expression. In summary, our data suggest that these changes could contribute to the metastatic spread of pancreatic cancer and may explain the devastating prognosis of this disease. [Cancer Res 2007;67(18):8633-42]

Porcupine expression is associated with the expression of S100P and other cancer-related molecules in non-small cell lung carcinoma

“…In addition, the increase in S100P has been revealed as a predictor of worse outcome of NSCLC patients (30). This clinical observation is explained by the supporting effect of S100P on cancer cell invasion in vitro and in vivo (23,30,(32)(33)(34)(35). One of the molecular mechanisms responsible for the increased expression of S100P in cancer cells is the DNA hypomethylation in 5'CpG islands of the s100P gene as identified for pancreatic and prostate cancer (42,43) and by our group for lung cancer (24).…”

“…S100P is reported as gene product involved in the initiation and invasion of cancer cells (23,24,(28)(29)(30)(31)(32)(33)(34)(35) as well as in the survival of cancer patients (30,33). Therefore, our further analyses focused on the interaction between the expression level of Porcupine and S100P in NSCLC.…”

Targeting S100P Inhibits Colon Cancer Growth and Metastasis by Lentivirus-Mediated RNA Interference and Proteomic Analysis

“…Extracellular S100P interacts with the receptor of advanced glycation end products (RAGE), which is associated with various cancers and stimulates Erk and nuclear factor (NF)-κB activity (13). Overexpression of S100P in pancreatic cancer Panc-1 cells protects cancer cells against cell death induced by chemotherapeutic 5-fluorouracil (5-FU) (3) and leads to increased S100A6 and cathepsin D expression, both of which are involved in cellular invasion (14). S100P also appears to function to increase gastric cancer growth and invasion of the cancer cells (15).…”

“…A wound-healing assay was performed as described (14). Assayed cells (1 × 10 6 ) were seeded on a six-well plate and cultured for 24 h. A scratch was made on the cell monolayer with a 200-μL pipette tip.…”

S100A6 binds to annexin 2 in pancreatic cancer cells and promotes pancreatic cancer cell motility

“…A number of proteins of the S100 family, including S100A2, S100A4, S100A6, S100A11 and S100P have been shown to be overexpressed in pancreatic cancer Shekouh et al, 2003;Vimalachandran et al, 2005;Ohuchida et al, 2006Ohuchida et al, , 2007a. In many cases, overexpression has been associated with enhanced invasion (Ohuchida et al, 2005;Suemizu et al, 2007;Whiteman et al, 2007) or poorer outcome (Vimalachandran et al, 2005;Oida et al, 2006;Ohuchida et al, 2007a). Virtually all S100 proteins act as Ca 2 þ sensors.…”