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Results: 1 to 6 of 6

Publication Record


Claudin-1 expression confers resistance to anoikis in colon cancer cells in a Src-dependent manner.
Singh AB, Sharma A, Dhawan P
(2012) Carcinogenesis 33: 2538-47
MeSH Terms: Anoikis, Cell Line, Tumor, Claudin-1, Colonic Neoplasms, Humans, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, src-Family Kinases
Show Abstract · Added March 7, 2014
Denial of the appropriate cell-matrix interaction in epithelial cells induces apoptosis and is called 'anoikis'. Cancer cells are resistant to anoikis and it is believed that the resistance to anoikis helps promote tumor malignancy especially metastasis. We and others have demonstrated that the expression of tight junction protein claudin-1 is highly upregulated in colorectal cancer (CRC) and helps promote tumor progression and metastasis. However, molecular mechanism/s underlying claudin-1-dependent regulation of CRC progression remains poorly understood. In current study, we have determined that claudin-1 expression modulates anoikis in colon cancer cells to influence colon cancer invasion and thus metastasis. We have further provided data that claudin-1 modulates anoikis in a Src-Akt-Bcl-2-dependent manner. Importantly, claudin-1 physically associates with Src/p-Src in a multiprotein complex that also includes ZO-1, a PDZ-binding tight junction protein. Taken together, our data support the role of claudin-1 in the regulation of CRC progression and suggest that the regulation of anoikis may serve as a key regulatory mechanism in claudin-1-dependent regulation of CRC progression. Our findings are of direct clinical relevance and may open new therapeutic opportunity in colon cancer treatment and/or management.
0 Communities
2 Members
0 Resources
8 MeSH Terms
The multifaceted actions of PTHrP in skeletal metastasis.
Soki FN, Park SI, McCauley LK
(2012) Future Oncol 8: 803-17
MeSH Terms: Anoikis, Apoptosis, Bone Neoplasms, Bone and Bones, Cell Movement, Cell Proliferation, Cellular Microenvironment, Humans, Hypercalcemia, Intercellular Signaling Peptides and Proteins, Parathyroid Hormone-Related Protein, Tumor Microenvironment
Show Abstract · Added March 5, 2014
PTHrP, identified during the elucidation of mediators of malignancy-induced hypercalcemia, plays numerous roles in normal physiology as well as pathological conditions. Recent data support direct functions of PTHrP in metastasis, particularly from tumors with strong bone tropism. Bone provides a unique metastatic environment because of mineralization and the diverse cell populations in the bone marrow. PTHrP is a key regulator of tumor-bone interactions and regulates cells in the bone microenvironment through proliferative and prosurvival activities that prime the 'seed' and the 'soil' of the metastatic lesion. This review highlights recent findings regarding the role of PTHrP in skeletal metastasis, including direct actions in tumor cells, as well as alterations in the bone microenvironment and future perspectives involving the potential roles of PTHrP in the premetastatic niche, and tumor dormancy.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Nuclear localization of parathyroid hormone-related peptide confers resistance to anoikis in prostate cancer cells.
Park SI, McCauley LK
(2012) Endocr Relat Cancer 19: 243-54
MeSH Terms: Animals, Anoikis, Bone Neoplasms, Cell Line, Tumor, Cell Nucleus, Gene Knockdown Techniques, Humans, Male, Mice, Mice, Nude, Neoplasm Transplantation, Parathyroid Hormone-Related Protein, Prostatic Neoplasms, Tumor Necrosis Factor-alpha
Show Abstract · Added March 5, 2014
Prostate cancer remains a leading cause of cancer-related death in men, largely attributable to distant metastases, most frequently to bones. Despite intensive investigations, molecular mechanisms underlying metastasis are not completely understood. Among prostate cancer-derived factors, parathyroid hormone-related peptide (PTHrP), first discovered as an etiologic factor for malignancy-induced hypercalcemia, regulates many cellular functions critical to tumor growth, angiogenesis, and metastasis. In this study, the role of PTHrP in tumor cell survival from detachment-induced apoptosis (i.e. anoikis) was investigated. Reduction of PTHLH (encoding PTHrP) gene expression in human prostate cancer cells (PC-3) increased the percentage of apoptotic cells when cultured in suspension. Conversely, overexpression of PTHrP protected prostate cancer cells (Ace-1 and LNCaP, both typically expressing low or undetectable basal PTHrP) from anoikis. Overexpression of nuclear localization signal (NLS)-defective PTHrP failed to protect cells from anoikis, suggesting that PTHrP-dependent protection from anoikis is an intracrine event. A PCR-based apoptosis-related gene array showed that detachment increased expression of the TNF gene (encoding the proapoptotic protein tumor necrosis factor-α) fourfold greater in PTHrP-knockdown PC-3 cells than in control PC-3 cells. In parallel, TNF gene expression was significantly reduced in PTHrP-overexpressing LNCaP cells, but not in NLS-defective PTHrP overexpressing LNCaP cells, when compared with control LNCaP cells. Subsequently, in a prostate cancer skeletal metastasis mouse model, PTHrP-knockdown PC-3 cells resulted in significantly fewer metastatic lesions compared to control PC-3 cells, suggesting that PTHrP mediated antianoikis events in the bloodstream. In conclusion, nuclear localization of PTHrP confers prostate cancer cell resistance to anoikis, potentially contributing to prostate cancer metastasis.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Claudin-1 up-regulates the repressor ZEB-1 to inhibit E-cadherin expression in colon cancer cells.
Singh AB, Sharma A, Smith JJ, Krishnan M, Chen X, Eschrich S, Washington MK, Yeatman TJ, Beauchamp RD, Dhawan P
(2011) Gastroenterology 141: 2140-53
MeSH Terms: Anoikis, Cadherins, Cell Line, Tumor, Claudin-1, Colonic Neoplasms, Disease Progression, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Immunoblotting, Membrane Proteins, Microarray Analysis, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcription Factors, Up-Regulation, Zinc Finger E-box-Binding Homeobox 1
Show Abstract · Added June 14, 2013
BACKGROUND & AIMS - Expression of the tight junction protein claudin-1 is dysregulated in colon tumors and associates with their progression. Up-regulation of claudin-1 reduces expression of E-cadherin. We investigated the mechanisms by which claudin-1 regulates E-cadherin expression and its effects in colon cancer cells.
MATERIALS AND METHODS - We used gene expression analysis, immunoblotting, and reverse transcription polymerase chain reaction to associate expression of the repressor of transcription Zinc Finger E-box binding homeobox-box1 (ZEB-1) with claudin-1. We analyzed SW480 colon cancer cells that overexpressed claudin-1, or SW620 cells in which claudin-1 expression was repressed, to determine the effects on ZEB-1 and E-cadherin expression, invasive activity, and resistance to anoikis. We studied cells that expressed constitutively active or dominant negative forms of factors in the Wnt or phosphotidylinositol-3-kinase signaling pathways and used pharmacologic inhibitors of these pathways to study their role in claudin-1-dependent regulation of ZEB-1. We used microarray analysis to examine gene expression patterns in 260 colorectal tumor and normal colon samples.
RESULTS - Claudin-1 down-regulates E-cadherin expression by up-regulating expression of ZEB-1. Claudin-1 activates Wnt and phosphotidylinositol-3-kinase/Akt signaling. ZEB-1 mediates claudin-1-regulated changes in cell invasion and anoikis. Expression of claudin-1 correlated with that of ZEB-1 in human colon tumor samples. In the progression from normal colonic epithelium to colon adenocarcinoma, levels of E-cadherin decreased, whereas levels of claudin-1 and ZEB-1 increased. Down-regulation of E-cadherin and up-regulation of ZEB-1 in colon tumors were associated with shorter survival times.
CONCLUSIONS - Claudin-1 up-regulates the repressor ZEB-1 to reduce expression of E-cadherin in colon cancer cells, increasing their invasive activity and reducing anoikis. This pathway is associated with colorectal cancer progression and patient survival.
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
2 Communities
3 Members
0 Resources
18 MeSH Terms
Protein phosphatase 2A (PP2A) holoenzymes regulate death-associated protein kinase (DAPK) in ceramide-induced anoikis.
Widau RC, Jin Y, Dixon SA, Wadzinski BE, Gallagher PJ
(2010) J Biol Chem 285: 13827-38
MeSH Terms: Amino Acid Substitution, Anoikis, Apoptosis Regulatory Proteins, Calcium-Calmodulin-Dependent Protein Kinases, Cell Adhesion, Ceramides, Cytoskeleton, Death-Associated Protein Kinases, HeLa Cells, Holoenzymes, Humans, Mutation, Missense, Phosphorylation, Protein Phosphatase 2, Tumor Suppressor Proteins
Show Abstract · Added March 26, 2014
The tumor suppressor, death-associated protein kinase (DAPK), is a Ca(2+)/calmodulin-regulated Ser/Thr kinase with an important role in regulating cytoskeletal dynamics. Autophosphorylation within the calmodulin-binding domain at Ser-308 inhibits DAPK catalytic activity. Dephosphorylation of Ser-308 by a previously unknown phosphatase enhances kinase activity and proteasome-mediated degradation of DAPK. In these studies, we identified two holoenzyme forms of protein phosphatase 2A (PP2A), ABalphaC and ABdeltaC, as DAPK-interacting proteins. These phosphatase holoenzymes dephosphorylate DAPK at Ser-308 in vitro and in vivo resulting in enhanced kinase activity of DAPK. The enzymatic activity of PP2A also negatively regulates DAPK levels by enhancing proteasome-mediated degradation of the kinase. Overexpression of wild type DAPK induces cell rounding and detachment in HEK293 cells; however, this effect is not observed following expression of an inactive DAPK S308E mutant. Finally, activation of DAPK by PP2A was found to be required for ceramide-induced anoikis. Together, our results provide a mechanism by which PP2A and DAPK activities control cell adhesion and anoikis.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Juxtacrine activation of epidermal growth factor (EGF) receptor by membrane-anchored heparin-binding EGF-like growth factor protects epithelial cells from anoikis while maintaining an epithelial phenotype.
Singh AB, Sugimoto K, Harris RC
(2007) J Biol Chem 282: 32890-901
MeSH Terms: Animals, Anoikis, Cell Differentiation, Cell Line, Cell Membrane, Cytoprotection, Dogs, Enzyme Activation, Epidermal Growth Factor, Epithelial Cells, ErbB Receptors, Gene Expression Regulation, Heparin-binding EGF-like Growth Factor, Intercellular Signaling Peptides and Proteins, Mitochondria, Phenotype, Phosphatidylinositol 3-Kinases, Protein Binding, Signal Transduction
Show Abstract · Added August 19, 2013
Loss of cell-matrix adhesion is often associated with acute epithelial injury, suggesting that "anoikis" may be an important contributor to cell death. Resistance against anoikis is a key characteristic of transformed cells. When nontransformed epithelia are injured, activation of the epidermal growth factor (EGF) receptor (EGFR) by paracrine/autocrine release of soluble ligands can induce a prosurvival program, but there is generally evidence for concomitant dedifferentiation. The EGFR ligand, heparin-binding EGF-like growth factor (HB-EGF), is synthesized as a membrane-anchored precursor that can activate the EGFR via juxtacrine signaling or can be released and act as a soluble growth factor. In Madin-Darby canine kidney cells, expression of membrane-anchored HB-EGF increases cell-cell and cell-matrix adhesion. Therefore, these studies were designed to test the effects of juxtacrine HB-EGF signaling upon cell survival and epithelial integrity when cells are denied proper cell-matrix interactions. Cells expressing a noncleavable mutated form of membrane-anchored HB-EGF demonstrated increased survival from anoikis, formed larger cell aggregates, and maintained epithelial characteristics even following prolonged detachment from the substratum. Physical association between membrane-anchored HB-EGF and EGFR was observed. Signaling studies indicated synergistic effects of EGFR activation and phosphatidylinositol 3-kinase signaling to regulate apoptotic and survival pathways. In contrast, although administration of exogenous EGF partially suppressed anoikis in wild type cells, it also led to an increased expression of mesenchymal markers, suggesting dedifferentiation. Taken together, we propose a novel role for membrane-anchored HB-EGF in the cytoprotection of epithelial cells.
1 Communities
2 Members
0 Resources
19 MeSH Terms