Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cells

Macleod, John; Hayes, Madeline; Pacheco, Ivan

doi:10.1152/ajpgi.00119.2007

Cited by 129 publications

(133 citation statements)

References 54 publications

(61 reference statements)

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“…30 In colon cancer also, Wnt5a can inhibit constitutively active b-catenin in activated protein Cemutated cells in an autocrine manner. 31 Wnt5a was also shown to decrease hepatocellular carcinoma growth in vitro, and many hepatocellular carcinoma tissues showed loss of Wnt5a and/or Ror2 expression that correlated with b-catenin stabilization, also supporting an antagonistic role of Wnt5a in b-catenin activation. 32,33 To directly address its role in hepatocytes, we generated cell Wnt5a conditional knockout mice.…”

Section: Wnt5a Inhibits B-catenin Signalingmentioning

confidence: 81%

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Yang

Cusimano

Monga

et al. 2015

The American Journal of Pathology

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Activation of Wnt/b-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased b-catenineT-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in b-catenineT-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression.In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of b-catenin signaling and hepatocyte proliferation, both in vitro and in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses b-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process. (Am J Pathol 2015, 185: 2194e2205; http:// dx

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Section: Wnt5a Inhibits B-catenin Signalingmentioning

confidence: 81%

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Yang

Cusimano

Monga

et al. 2015

The American Journal of Pathology

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“…Upon activation, the cytoplasmic tail of Ecadherin interacts with ß-catenin, preventing ß-catenin translocation to nucleus where it forms a complex with TCF4 (36,38). Formation and activation of ß-catenin/TCF4 are prominent in driving the malignant progression of colon cancer (36,37). Calcipotriol and lentinan suppressed the expression of survivin and TS through induction of CaSR in the human colon carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

Effects of potential calcium sensing receptor inducers on promoting chemosensitivity of human colon carcinoma cells

Liu¹

2010

Int J Oncol

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Abstract.We have previously reported that by inducing calcium sensing receptor (CaSR), calcitriol, the active form of vitamin D, promoted the sensitivity of the human colon carcinoma cells to anticancer drugs. In the current study we tested several other potential CaSR modulators, calcipotriol and the effective components of Chinese herbal medicine lentinan, for their functions in inducing CaSR expression in human colon carcinoma cell line CBS, Moser, Fet, and SW480 cells and subsequently promoting sensitivity of the cells to anticancer drugs. Calcipotriol and lentinan suppressed invasion of the colon carcinoma cells and enhanced the cytotoxicity of anticancer regimen FOLFIRI to cells in culture or in anchorage-independent growth. In the mechanism study we found that calcipotriol and lentinan suppressed protein expression and gene transcriptional activities of survivin and thymidylate synthase, increased E-cadherin cell membrane localization and complex formation of E-cadherin and ß-catenin, and repressed TCF4 transcriptional activation. These effects were attenuated, however, in CaSR knocked-down cells, indicating that CaSR was required in the pathway. We concluded that calcipotriol and lentinan are efficient in promoting chemosensitivity in colon carcinoma cells. Since both compounds have much less side effects than calcitriol in clinic, they have greater potential to be applied as supplements of colon cancer therapy. IntroductionCaSR is a G protein-coupled receptor originally identified in human parathyroid gland where it senses the instant changes in extracellular Ca 2+ levels (1). It was discovered later that CaSR is also expressed in a wide variety of human tissues, including human colon cancer and other cancer cells (2-4). The potential function of CaSR in colon epithelium is involved in promoting the progress of cell differentiation. In normal colon epithelium, there is no CaSR expression at the bottom of the colonic crypts where undifferentiated stem cells are located and responsible for epithelial tissue renewal (5,6). As the epithelial cells differentiate and migrate upward to the top of the crypt, the cells acquire a gradient increase in the expression of the CaSR (5,6). In colon cancer, welldifferentiated carcinoma cells express observable levels of CaSR, whereas undifferentiated carcinoma cells have little or no CaSR expression (7-10). Since undifferentiated status is one of the mechanisms underlying drug resistance, we have hypothesized in our previous studies that CaSR is involved in chemosensitivity of human colon carcinoma cells and found that activation or induction of CaSR in the cells significantly promoted the sensitivity of the cells to anticancer drug treatment (11,12).The human CaSR gene has two promoters (P1 and P2) and each promoter has a transcriptional start site (4,13-15). Both promoters contain the vitamin D (VD) response element (VDRE), which is recognized and bound by the complex of VD receptor (VDR) activated and bound by VD (15). Through this mechanism, VD induces P1 and P2 pro...

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“…Furthermore, Ca 2 þ influx can trigger various cellular signaling pathways, such as Wnt, Notch, and ERK1/2. [28][29][30] In this study, we aimed to identify the role of Ca 2 þ homeostasis in POS phagorytosis in RPE cells. As shown in Figure 2, CFI was significantly increased as indicated by LSCM and FCM especially at 12 h. Lipofuscin accumulated in RPE cells fed with POS especially at 4 days (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Calcium overload is associated with lipofuscin formation in human retinal pigment epithelial cells fed with photoreceptor outer segments

Zhang

et al. 2011

Eye

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Purpose To investigate the role of Ca 2 þ in lipofuscin formation in human retinal pigment epithelial (RPE) cells that phagocytize bovine photoreceptor outer segments (POSs). Methods Cultured human RPE cells fed with 2 Â 10 7 per l bovine POS were treated with flunarizine, an antagonist of Ca 2 þ channel, or/and centrophenoxine, a lipofuscin scavenger. The Ca 2 þ changes and lipofuscin formation were measured with fluoresence dye Fluo-3/AM ester, laser scanning confocal microscopy (LSCM) and flow cytometry (FCM). The activity of RPE cells was measured by methyl thiazolyl tetrazolium (MTT) assay and argyrophilic nucleolar organizer regions (AgNORs) assay. Results The Ca 2 þ fluorescence intensity (CFI) of RPE cells fed with POS was significantly increased compared with the controls (165.36±29.92 U). It reached a peak with 777.33±63.86 U (Po0.01) at 12 h, and then decreased but still maintained a high level of 316.90 ± 36.07 U (Po0.01) for 4 days. Flunarizine and centrophenoxine significantly decreased the Ca 2 þ overload to 227.18 ± 14.00 U at 12 h and 211.06 ± 20.45 U at 4 days. FCM confirmed these changes. The drugs also showed an inhibitory effect on the lipofuscin formation. The proliferation rate of the cells fed with POS increased significantly. Both drugs had inhibitory effects on the activity of the cultured cells. This tendency was confirmed by AgNORs assay. Conclusions The Ca 2 þ inflow initiated lipofuscin accumulation in RPE cells fed with POS. Flunarizine and centrophenoxine can decrease Ca 2 þ overload and lipofuscin formation in RPE cells, accompanied by maintaining cellular vitality.

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Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cells

Abstract: MacLeod RJ, Hayes M, Pacheco I. Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective

Cited by 129 publications

References 54 publications

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Effects of potential calcium sensing receptor inducers on promoting chemosensitivity of human colon carcinoma cells

Calcium overload is associated with lipofuscin formation in human retinal pigment epithelial cells fed with photoreceptor outer segments

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