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Zeng H.,U.S. Department of Agriculture | Briske-Anderson M.,U.S. Department of Agriculture | Wu M.,University of North Dakota | Moyer M.P.,INCELL Corporation
Nutrition and Cancer | Year: 2012

Methylselenol is hypothesized to be a critical selenium metabolite for anticancer action, and differential chemopreventive effects of methylselenol on cancerous and noncancerous cells may play an important role. In this study, the submicromolar concentrations of methylselenol were generated by incubating methionase with seleno-L methionine, and colon-cancer-derived HCT-116 cells and noncancerous colon NCM460 cells were exposed to methylselenol. Methylselenol exposure inhibited cell growth and led to an increase in G1 and G2 fractions with a concomitant drop in S-phase and an induction of apoptosis in HCT116, but to a much lesser extent in NCM460 colon cells. Similarly, the examination of mitogen-activated protein kinase (MAPK) and cellular myelocytomatosis oncogene (c-Myc) signaling status revealed that methylselenol inhibited the phosphorylation of extracellular-regulated kinase1/2 and p38 mitogen-activated protein kinase and the expression of c-Myc in HCT116 cells, but also to a lesser extent in NCM460 cells. The other finding is that methylselenol inhibits sarcoma kinase phosphorylation in HCT116 cells. In contrast, methylselenol upregulated the phosphorylation of sarcoma and focal adhesion kinase survival signals in the noncancerous NCM460 cells. Collectively, methylselenol's stronger potential of inhibiting cell proliferation/survival signals in the cancerous HCT116 cells when compared with that in noncancerous NCM460 cells may partly explain the potential of methylselenol's anticancer action. © 2012 Copyright Taylor and Francis Group, LLC.


Rey O.,University of California at Los Angeles | Young S.H.,University of California at Los Angeles | Jacamo R.,University of Texas M. D. Anderson Cancer Center | Moyer M.P.,INCELL Corporation | Rozengurt E.,University of California at Los Angeles
Journal of Cellular Physiology | Year: 2010

The extracellular Ca 2+-sensing receptor (CaR) is increasingly implicated in the regulation of multiple cellular functions in the gastrointestinal tract, including secretion, proliferation and differentiation of intestinal epithelial cells. However, the signaling mechanisms involved remain poorly defined. Here we examined signaling pathways activated by the CaR, including Ca 2+ oscillations, in individual human colon epithelial cells. Single cell imaging of colon-derived cells expressing the CaR, including SW-480, HT-29, and NCM-460 cells, shows that stimulation of this receptor by addition of aromatic amino acids or by an elevation of the extracellular Ca 2+ concentration promoted striking intracellular Ca 2+ oscillations. The intracellular calcium oscillations in response to extracellular Ca 2+ were of sinusoidal pattern and mediated by the phospholipase C/diacylglycerol/inositol 1,4,5-trisphosphate pathway as revealed by a biosensor that detects the accumulation of diacylglycerol in the plasma membrane. The intracellular calcium oscillations in response to aromatic amino acids were of transient type, that is, Ca 2+ spikes that returned to baseline levels, and required an intact actin cytoskeleton, a functional Rho, Filamin A and the ion channel TRPC1. Further analysis showed that re-expression and stimulation of the CaR in human epithelial cells derived from normal colon and from colorectal adenocarcinoma inhibits their proliferation. This inhibition was associated with the activation of the signaling pathway that mediates the generation of sinusoidal, but not transient, intracellular Ca 2+ oscillations. Thus, these results indicate that the CaR can function in two signaling modes in human colonic epithelial cells offering a potential link between gastrointestinal responses and food/nutrients uptake and metabolism. © 2010 Wiley-Liss, Inc.


Norbury K.C.,An Acelity Company | Moyer M.P.,INCELL Corporation
Mediators of Inflammation | Year: 2015

In a swine model of ischemia/reperfusion injury coupled with sepsis, we have previously shown attenuation of secondary organ injury and decreased mortality with negative pressure therapy (NPT). We hypothesized that NPT modulates the intestinal microenvironment by mediating the innate immune system. Sepsis was induced in 12 anesthetized female pigs. Group 1 (n = 6) was decompressed at 12 hrs after injury (T12) and treated with standard of care (SOC), and group 2 (n = 6) with NPT for up to T48. Immunoparalysis was evident as lymphocytopenia at T24 in both groups; however, survival was improved in the NPT group versus SOC (Odds ratio = 4.0). The SOC group showed significant reduction in lymphocyte numbers compared to NPT group by T48 (p < 0.05). The capacity of peritoneal fluid to stimulate a robust reactive oxygen species response in vitro was greater for the NPT group, peaking at T24 for both M1 (p = 0.0197) and M2 macrophages (p = 0.085). Plasma elicited little if any effect which was confirmed by microarray analysis. In this septic swine model NPT appeared to modulate the intestinal microenvironment, facilitating an early robust, yet transient, host defense mediated by M1 and M2 macrophages. NPT may help overcome immunoparalysis that occurs during inflammatory response to septic injury. © 2015 Kenneth C. Norbury and Mary Pat Moyer.


Wang F.,Shanghai JiaoTong University | Yang Y.-Z.,Shanghai JiaoTong University | Shi C.-Z.,Shanghai JiaoTong University | Zhang P.,Shanghai JiaoTong University | And 4 more authors.
Annals of Surgical Oncology | Year: 2012

Purpose: To investigate whether ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) expression is upregulated in colorectal cancer (CRC), whether UHRF1 promotes CRC cell growth and migration and the underlying molecular mechanism. Methods: UHRF1 protein expression was determined in 144 pairs of primary CRC and their corresponding adjacent nontumor tissues by immunohistochemistry with tissue microarrays. UHRF1 mRNA expression was assessed in 20 pairs of the above tissues and four colon cancer cell lines by quantitative reverse transcriptase-polymerase chain reaction. Associations of UHRF1 expression with demographic and clinicopathologic features were determined. Additionally, the effects of lentiviral-mediated RNA interference (RNAi) of UHRF1 on cell proliferation and migration, cell cycle and apoptosis, and the expression of p16ink4a and p21waf1/cip1 were investigated in CRC cell lines. Results: UHRF1 was overexpressed in CRC tissues and cell lines. UHRF1 protein expression levels correlated with the presence of lymph nodes (P = 0.005), distal metastasis (P = 0.030), poor Dukes staging (P = 0.001), and absence of p16ink4a expression (P = 0.002). RNAi of UHRF1 inhibited proliferation and migration, and induced apoptosis and cell cycle arrest at the G0/G1 phase. Furthermore, RNAi of UHRF1 enhanced the expression of p16ink4a, but not p21waf1/cip1, in CRC cells. Conclusions: UHRF1 expression is upregulated in CRC and is associated with the progression of CRC. Moreover, RNAi of UHRF1 decreases proliferation and migration but enhances apoptosis of CRC cells, with increased p16 ink4a expression. UHRF1 promotes CRC growth and metastasis, likely by repressing p16ink4a, and thus it may be used as a biomarker or even a therapeutic target for CRC. © 2012 Society of Surgical Oncology.


Zeng H.,U.S. Department of Agriculture | Trujillo O.N.,University of Arizona | Moyer M.P.,INCELL Corporation | Botnen J.H.,U.S. Department of Agriculture
Nutrition and Cancer | Year: 2011

Sulforaphane (SFN) is a naturally occurring chemopreventive agent; the induction of cell cycle arrest and apoptosis is a key mechanism by which SFN exerts its colon cancer prevention. However, little is known about the differential effects of SFN on colon cancer and normal cells. In this study, we demonstrated that SFN (15 μmol/L) exposure (72 h) inhibited cell proliferation by up to 95% in colon cancer cells (HCT116) and by 52% in normal colon mucosa-derived (NCM460) cells. Our data also showed that SFN exposure (5 and 10 μmol/L) led to the reduction of G1 phase cell distribution and an induction of apoptosis in HCT116 cells, but to a much lesser extent in NCM460 cells. Furthermore, the examination of mitogen-activated protein kinase (MAPK) signaling status revealed that SFN upregulated the phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) in NCM460 cells but not in HCT116 cells. In contrast, SFN enhanced the phosphorylation of stress-activated protein kinase (SAPK) and decreased cellular myelocytomatosis oncogene (c-Myc) expression in HCT116 cells but not NCM460 cells. Taken together, the activation of survival signaling in NCM460 cells and apoptotic signaling in HCT116 cells may play a critical role in SFN's stronger potential of inhibiting cell proliferation in colon cancer cells than in normal colon cells. Copyright © 2011, Taylor & Francis Group, LLC.

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