Selective COX-2 inhibitor (celecoxib) decreases cellular growth in prostate cancer cell lines independent of p53.

Celecoxib is a clinically available COX-2 inhibitor that has been reported to have antineoplastic activity. It has been proposed as a preventative agent for several types of early neoplastic lesions. Earlier studies have shown that sensitivity of prostatic carcinoma (PCa) to celecoxib is associated with apoptosis; however, these studies have not demonstrated adequately whether this effect is dependent on p53 status. We studied the relation between sensitivity to celecoxib and the phenotypic p53 status of PCa cells lines, LNCaP (wild type p53), PC3 (null p53) and DU145 (mutated p53). Cellular growth was assessed at 24, 48, 72 and 96 h after celecoxib treatment at concentrations of 0, 10, 30, 50, 70 and 100 µM using an MTT assay. Cellular proliferation (Ki-67 expression) was determined by immunocytochemistry. Phenotypic expression of p53 was analyzed by western blotting. The effects of celecoxib on cellular growth and its association with p53 were assessed after down-regulation of p53 using synthetic interfering RNAs (siRNA) in LNCaP cells. Expression of p53 and COX-2 at mRNA levels was assessed by quantitative real time polymerase reaction (qRT-PCR). We found that celecoxib inhibited cellular growth and proliferation in a dose-dependent manner in all three cell lines; LNCaP cells with a native p53 were the most sensitive to celecoxib. We observed a down- regulation effect on p53 in LNCaP cells exposed to ≥ 30 µM celecoxib for 72 h, but found no significant changes in the p53 levels of DU145 cells, which have a mutated p53. Reduced COX-2 expression was found with decreased p53 in LNCaP and PC-3 cells that were exposed to ≥ 20 µM of celecoxib for 72 h, but COX-2 expression was increased in DU145 cells. All three cell lines demonstrated pan-cytotoxicity when exposed to 100 µM celecoxib. When p53 expression was inhibited using siRNA in LNCaP cells, the inhibitory effects on cellular growth usually exerted by celecoxib were not changed significantly. Celecoxib reduces the growth of prostate cancer cell lines in part by decreasing proliferation, which suggests that the inhibition of growth of LNCaP cells by celecoxib is independent of normal levels of native p53.

Immunohistochemical expression of rabphilin-3A-like (Noc2) in normal and tumor tissues of human endocrine pancreas.

Involvement of rabphilin-3A-like (RPH3AL), or Noc2, the potential effector of Ras-associated binding proteins Rab3A and Rab27A in the regulation of exocytotic processes in the endocrine pancreas has been demonstrated in experimental models. Noc2 expression together with other regulatory molecules of the exocytotic machinery in human tissues, however, has not been studied. We evaluated immunohistochemical expression of the key molecules of the exocytotic machinery, Noc2, Rab3A, Rab27A, and RIM2, together with the characteristic islet cell hormones, insulin and glucagon in normal and endocrine tumor tissues of human pancreas. Normal pancreatic islets were stained for all of these proteins and showed strong cytoplasmic localization. A similar pattern of strong cytoplasmic expression of these proteins was observed in the majority of endocrine tumors. By contrast, the exocrine portions of normal appearing pancreas completely lacked Rab27A staining and showed decreased expression of the proteins, Noc2, Rab3A, and RIM2. The staining pattern of Noc2 and Rab27A was similar to the staining pattern of glucagon-producing cells within the islets. The concomitant expression of Noc2 with these molecules suggests that Noc2 may serve as an effector for Rab3A and Rab27A and that it is involved in the regulation of exocytosis of the endocrine pancreas in humans.

Colorectal cancer and hypercholesterolemia: review of current research.

AIM: In spite of ample research about a high level of cholesterol in the blood of patients with colorectal cancer (CRC), the relationship between factors causing hypercholesterolemia and factors leading to CRC development is not fully investigated. The purpose of this article is to provide a review of the current research about the risk factors leading to the development of hypercholesterolemia and CRC, and to show the relationship between these factors, hypercholesterolemia and CRC with the implication for CRC preventive and treatment practices. METHODS: A systematic search of MEDLINE and PUBMED databases between 1990 and 2005 was conducted to locate the studies that investigated the risk factors causing CRC and hypercholesterolemia. From among 255 studies found, 66 were selected that matched the following criteria for selection: (1) reported original research; (2) discussed at least one of the listed eight factors; (3) discussed hypercholesterolemia; and/or (4) discussed colon or rectum cancer. RESULTS: The studies were grouped according to four areas of research: (1) studies that explored the relationship between different factors and CRC incidences; (2) studies that investigated the relationship between different factors and CRC incidences and the role of mutations in causing CRC; (3) studies that looked at the factors causing hypercholesterolemia; and (4) studies that explored the relationship among the factors, hypercholesterolemia, and CRC development. A discussion of the studies is presented and the details related to the studies major aspects are summarized in 4 tables. CONCLUSION: The review has revealed a relationship between factors that can lead to the development of CRC and those that lead to hypercholesterolemia. Although the role of many individual risk factors is still controversial the analysis of their significance in combination might be important for diagnostic and development of the models for prediction of cancer occurrence.