Cyclooxygenase (COX) and its prostanoid metabolites have been implicated in the control of cell survival; however, their role as mitogens remains undefined. To better understand the role of prostanoids on cell growth, we used mouse colon adenocarcinoma (CT26) cells to investigate the role of prostaglandin E 2 (PGE 2 ) in cell proliferation. CT26 cells express both COX1 and COX2 and metabolize arachidonic acid to PGE 2. Treatment with indomethacin, or COXselective inhibitors, prevents PGE 2 biosynthesis and CT26 cell proliferation. The anti-proliferative effects of COX inhibition are rescued specifically by treatment with PGE 2 or the EP4 receptor-selective agonist PGE 1 -OH via phosphatidylinositol 3-kinase/extracellular signal-regulated kinase (ERK) activation, thus providing a functional link between PGE 2 -induced cell proliferation and EP4-mediated ERK signaling. Indomethacin or COX2 inhibitors, but not COX1 inhibitors, reduced the size and number of CT26-derived tumors in vivo. These inhibitory effects are paralleled by marked declines in the levels of tumor PGE 2 , suggesting that their anti-tumor effects are directly associated with the inhibition of COX2 enzymatic activity. The described anti-tumor effects of indomethacin are evident whether it is administered at the time of, or 7 days after, tumor cell injection, suggesting that it has tumor preventive and therapeutic actions. Furthermore, the observation that indomethacin increases the survival rates of tumor-bearing mice, even after withdrawal of the drug, indicates that its effects are long lasting and that it may be potentially useful for the prevention and the clinical management of human cancers.The identification of cyclooxygenase (COX) 1 as the target for non-steroidal anti-inflammatory drugs (NSAIDs) led to new understandings of its pathophysiological role and of the mechanisms of action of these drugs (1, 2). The discovery of COX2, an isoform that, although catalytically identical to COX1, shows inducible tissue-selective expression, suggested physiological and pathophysiological roles for the constitutively expressed (COX1) and inducible (COX2) isoforms, respectively (1-4). Studies showing a correlation between NSAIDs and decreased colon cancer incidence, and the demonstration of up-regulated COX2 expression in colon carcinoma, suggested a role for COX2 in the pathophysiology of colon cancer and created new paradigms for the study of the role of prostanoids in cancer (1-3). Nevertheless, despite extensive supporting evidence, direct links between the anti-tumor effects of NSAIDs and COX inhibition are yet to be established (4 -9). The potential for non-COX-dependent anti-tumor effects of NSAIDs (6 -9), as well as limited evidence available identifying a specific prostanoid(s) as the mediator responsible for the anti-tumor effects of the COX inhibitors (5), raised questions regarding the mechanism of action of NSAIDs and of the role of arachidonic acid, prostanoids, and COXs in human cancer (4 -9).During studies of arachidonic acid metabolism ...

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Excessive glomerular collagen IV and reactive oxygen species (ROS) production are key factors in the development of diabetic nephropathy. Integrin alpha1beta1, the major collagen IV receptor, dowregulates collagen IV and ROS production, suggesting this integrin might determine the severity of diabetic nephropathy. To test this possibility, wild-type and integrin alpha1-null mice were rendered diabetic with streptozotocin (STZ) (100 mg/kg single intraperitoneal injection), after which glomerular filtration rate (GFR), glomerular collagen deposition, and glomerular basement membrane (GBM) thickening were evaluated. In addition, ROS and collagen IV production by mesangial cells as well as their proliferation was measured in vitro. Diabetic alpha1-null mice developed worse renal disease than diabetic wild-type mice. A significant increase in GFR was evident in the alpha1-null mice at 6 weeks after the STZ injection; it started to decrease by week 24 and reached levels of non-diabetic mice by week 36. In contrast, GFR only increased in wild-type mice at week 12 and its elevation persisted throughout the study. Diabetic mutant mice also showed increased glomerular deposition of collagen IV and GBM thickening compared to diabetic wild-type mice. Primary alpha1-null mesangial cells exposed to high glucose produced more ROS than wild-type cells, which led to decreased proliferation and increased collagen IV synthesis, thus mimicking the in vivo finding. In conclusion, this study suggests that lack of integrin alpha1beta1 exacerbates the glomerular injury in a mouse model of diabetes by modulating GFR, ROS production, cell proliferation, and collagen deposition.

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Objective measurements and their intersection with subjective perceptions demonstrate the influences of inter-generation, season, sex, and living habits on Chinese body skin.

The collagen IV binding receptor integrin A1B1 has been shown to regulate lung cancer due to its proangiogenic properties; however, it is unclear whether this receptor also plays a direct role in promoting primary lung tumors. To investigate this possibility, integrin A1-null mice were crossed with KrasLA2 mice that carry an oncogenic mutation of the Kras gene (G12D) and develop spontaneous primary tumors with features of non-small cell lung cancer. We provide evidence that KrasLA2/A1-null mice have a decreased incidence of primary lung tumors and longer survival compared with KrasLA2/A1 wild-type controls. Tumors from KrasLA2/A1-null mice were also smaller, less vascularized, and exhibited reduced cell proliferation and increased apoptosis, as determined by proliferating cell nuclear antigen and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end staining, respectively. Moreover, tumors from the KrasLA2/A1-null mice showed diminished extracellular signal-regulated kinase (ERK) but enhanced p38 mitogenactivated protein kinase activation. Primary lung tumor epithelial cells isolated from KrasLA2/A1-null mice showed a significant decrease in anchorage-independent colony formation, collagen-mediated cell proliferation, ERK activation, and, most importantly, tumorigenicity when injected into nude mice compared with KrasLA2/A1 wild-type tumor cells. These results indicate that loss of the integrin A1 subunit decreases the incidence and growth of lung epithelial tumors initiated by oncogenic Kras, suggesting that both Kras and integrin A1B1 cooperate to drive the growth of non-small cell lung cancer in vivo. [Cancer Res 2008;68(15):6127-9]