Sequential Down-regulation of E-Cadherin with Squamous Cell Carcinoma Progression: Loss of E-Cadherin via a Prostaglandin E2-EP2–Dependent Posttranslational Mechanism

Brouxhon, Sabine M.; Kyrkanides, Stephanos; O’Banion, M. Kerry; Johnson, Renée; Pearce, David A.; Centola, Grace M.; Miller, Jen-nie H.; McGrath, Kieran H.; Erdle, Brandon; Scott, Glynis; Schneider, Sandra; VanBuskirk, JoAnne; Pentland, Alice P.

doi:10.1158/0008-5472.can-06-4415

Cited by 54 publications

(85 citation statements)

References 44 publications

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“…Recent work in cell culture has shown that chemical or antisense interference with the prostaglandin signaling pathway components results in decreased Snai1 transcription and increased E-cadherin protein levels (Dohadwala et al, 2006;Brouxhon et al, 2007). However, our qRT-PCR and whole-mount ISH analyses showed that snai1a and snai1b levels were not significantly different in ptges versus control morphants ( Fig.…”

Section: Snai1a Protein Expression Is Stabilized In the Presence Of Pmentioning

confidence: 58%

Prostaglandin Gβγ signaling stimulates gastrulation movements by limiting cell adhesion through Snai1a stabilization

et al. 2010

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SUMMARYGastrulation movements form the germ layers and shape them into the vertebrate body. Gastrulation entails a variety of cell behaviors, including directed cell migration and cell delamination, which are also involved in other physiological and pathological processes, such as cancer metastasis. Decreased Prostaglandin E 2 (PGE 2 ) synthesis due to interference with the Cyclooxygenase (Cox) and Prostaglandin E synthase (Ptges) enzymes halts gastrulation and limits cancer cell invasiveness, but how PGE 2 regulates cell motility remains unclear. Here we show that PGE 2 -deficient zebrafish embryos, impaired in the epiboly, internalization, convergence and extension gastrulation movements, exhibit markedly increased cell-cell adhesion, which contributes to defective cell movements in the gastrula. Our analyses reveal that PGE 2 promotes cell protrusive activity and limits cell adhesion by modulating E-cadherin transcript and protein, in part through stabilization of the Snai1a (also known as Snail1) transcriptional repressor, an evolutionarily conserved regulator of cell delamination and directed migration. We delineate a pathway whereby PGE 2 potentiates interaction between the receptor-coupled G protein  subunits and Gsk3 to inhibit proteasomal degradation of Snai1a. However, overexpression of -catenin cannot stabilize Snai1a in PGE 2 -deficient gastrulae. Thus, the Gsk3-mediated and -catenin-independent inhibition of cell adhesion by Prostaglandins provides an additional mechanism for the functional interactions between the PGE 2 and Wnt signaling pathways during development and disease. We propose that ubiquitously expressed PGE 2 synthesizing enzymes, by promoting the stability of Snai1a, enable the precise and rapid regulation of cell adhesion that is required for the dynamic cell behaviors that drive various gastrulation movements.

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Section: Snai1a Protein Expression Is Stabilized In the Presence Of Pmentioning

confidence: 58%

Prostaglandin Gβγ signaling stimulates gastrulation movements by limiting cell adhesion through Snai1a stabilization

et al. 2010

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“…In the present study, several hundreds of genes showed changed expression in the tumor tissues from the EP2-knockout mice compared with tumor tissues from the wild-type mice. A reason for this could be that EP2 signaling in host tissues is involved in several different pathways that are important events in tumor cells associated with tumor progression, including angiogenesis, the upregulation of COX-2, the loss of E-cadherin expression and anti-apoptosis in stem cells (16,22,(25)(26)(27)(28). Prom-1, also known as CD133, and CD44 are well-known markers of cancer stem cells, indicating reduced gene expression in the tumor tissues from the EP2-knockout mice in the present study.…”

Section: Discussionmentioning

confidence: 99%

Host knockout of E-prostanoid 2 receptors reduces tumor growth and causes major alterations of gene expression in prostaglandin E2-producing tumors

et al. 2016

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Abstract. Prostaglandin E 2 (PGE 2 ) is elevated in a variety of malignant tumors and has been shown to affect several hallmarks of cancer. Accordingly, the PGE 2 receptor, E-prostanoid 2 (EP2), has been reported to be associated with patient survival and reduced tumor growth in EP2-knockout mice. Thus, the aim of the present study was to screen for major gene expression alterations in tumor tissue growing in EP2-knockout mice. EP2-knockout mice were bred and implanted with EP2 receptor-expressing and PGE 2 -producing epithelial-like tumors. Tumor tissue and plasma were collected and used for analyses with gene expression microarrays and multiplex enzyme-linked immunosorbent assays. Tumor growth, acute phase reactions/systemic inflammation and the expression of interleukin-6 were reduced in EP2-knockout tumor-bearing mice. Several hundreds of genes displayed major changes of expression in the tumor tissue when grown in EP2-knockout mice. Such gene alterations involved several different cellular functions, including stemness, migration and cell signaling. Besides gene expression, several long non-coding RNAs were downregulated in the tumors from the EP2-knockout mice. Overall, PGE 2 signaling via host EP2 receptors affected a large number of different genes involved in tumor progression based on signaling between host stroma and tumor cells, which caused reduced tumor growth.

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“…Mice bearing tumors, with an estimated volume of 100 mm 3 were subsequently randomized to receive a one-time injection of saline (n ¼ 6), IgG (10 mg/kg, n ¼ 6), or anti-sEcad mAb (10 mg/kg, n ¼ 7) and tumor growth was monitored for an additional 20 days. Starting from 12 days, anti-sEcad treatment demonstrated a significant decrease in tumor volume and burden compared with controls ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although the best known function of PTEN involves the dephosphorylation of PtdIns (3,4,5)P3 at the plasma membrane surface, cytoplasmic PTEN has been shown to inhibit cell proliferation (38). Moreover, nuclear PTEN has been proposed to regulate the cell cycle through the suppression of cyclin D1 activity (49).…”

Section: Discussionmentioning

confidence: 99%

“…E-cadherin belongs to a family of integral transmembrane glycoproteins that promote the establishment of calcium-dependent homotypic cell-cell adhesions. Using a chronic photocarcinogenesis model, we have previously demonstrated a sequential ultraviolet (UV)-induced loss of membrane-bound E-cadherin with progression from normal epithelium to dysplastic lesions, papillomas, and overt SCCs (3). Moreover, we have found a concomitant increase in E-cadherin mRNA and a progressive increase in the shedding of the E-cadherin extracellular domain fragment (termed sEcad), suggesting that posttranslational processing of E-cadherin via ectodomain shedding plays an important role in UV-induced skin carcinogenesis (4).…”

Section: Introductionmentioning

confidence: 99%

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Ectodomain-Specific E-Cadherin Antibody Suppresses Skin SCC Growth and Reduces Tumor Grade: A Multitargeted Therapy Modulating RTKs and the PTEN–p53–MDM2 Axis

Brouxhon¹,

Kyrkanides²,

Raja³

et al. 2014

Molecular Cancer Therapeutics

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Tumor cell survival consists of an intricate balance between cell growth and cell death pathways involving receptor tyrosine kinases [RTK; i.e., HER1-4, insulin-like growth factor-1 receptor (IGF-1R), etc.], MDM2, and the tumor suppressor proteins phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p53. We recently demonstrated that shedded E-cadherin extracellular domain fragment (sEcad) is a valid oncogenic target that is significantly increased in human clinical skin squamous cell cancers (SCC) samples, UV-induced mouse tumors, and cells and promotes tumor cell proliferation, migration, and invasion by interacting and activating with the HER-phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) and mitogenactivated protein kinase (MAPK) axis. In resected human SCC tumors, we reported enhanced sEcad-HER1, sEcad-HER2, and sEcad-IGF-1R, but not FL-Ecad-RTK interactions. Here, we demonstrate that a sEcad antibody against the ectodomain of E-cadherin suppressed SCC growth and increased tumor differentiation in orthotopic cutaneous SCC xenografts by inhibiting proliferation and inducing apoptosis. A similar anti-sEcad antibodyinduced inhibition of proliferation and induction of cell death was evident in PAM212 cells in vitro. Mechanistically, anti-sEcad administration upregulated an array of cell death pathways (i.e., Bad, active caspase-3, and cleaved PARP) and inhibited inhibitors of apoptosis (IAP; survivin, livin, etc.), RTKs (HER1, HER2, p95HER2, and IGF-1R), MAPK and PI3K/mTOR prosurvival signaling. Interestingly, in anti-sEcad mAb-treated tumors and PAM212 cells, this effect was associated with a profound increase in membrane, cytosolic, and nuclear levels of PTEN; enhanced cytosolic p53; and a decrease in MDM2 levels. Overall, our studies suggest that an antibodybased therapy against sEcad may be a novel therapeutic platform for cutaneous SCCs by hampering key protooncogenes (RTKs, IAPs, and MDM2) and activating potent tumor suppressor proteins (PTEN and p53) intricately linked to tumor growth and survival.

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Sequential Down-regulation of E-Cadherin with Squamous Cell Carcinoma Progression: Loss of E-Cadherin via a Prostaglandin E2-EP2–Dependent Posttranslational Mechanism

Cited by 54 publications

References 44 publications

Prostaglandin Gβγ signaling stimulates gastrulation movements by limiting cell adhesion through Snai1a stabilization

Prostaglandin Gβγ signaling stimulates gastrulation movements by limiting cell adhesion through Snai1a stabilization

Host knockout of E-prostanoid 2 receptors reduces tumor growth and causes major alterations of gene expression in prostaglandin E2-producing tumors

Ectodomain-Specific E-Cadherin Antibody Suppresses Skin SCC Growth and Reduces Tumor Grade: A Multitargeted Therapy Modulating RTKs and the PTEN–p53–MDM2 Axis

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