Modulation of the Tumor Suppressor Protein α-Catenin by Ischemic Microenvironment

Plumb, Claire; Adamcic, Una; Shahrzad, Siranoush; Minhas, Kanwal; Adham, Sirin A.; Coomber, Brenda L.

doi:10.2353/ajpath.2009.090007

Cited by 8 publications

(8 citation statements)

References 57 publications

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“…Our corroborative data further revealed the absence of α-catenin in DLD-1 single cells in contrast to DLD-1 cell clusters ( Fig. 2B ) ( 26 , 29 ). Accordingly, the subpopulations were termed as DLD-1 α-cat (epithelioid or forming cell clusters in col-I) and DLD-1 Δα-cat (round or forming single cell groups in col-I).…”

Section: Resultssupporting

confidence: 79%

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Differential effects of α-catenin on the invasion and radiochemosensitivity of human colorectal cancer cells

et al. 2018

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Driven by genetic and epigenetic alterations, progression, therapy resistance and metastasis are frequent events in colorectal cancer (CRC). Although often speculated, the function of cell-cell contact for radiochemosensitivity, particularly associated with E-cadherin/catenin complex, warrants further clarification. In this study, we investigated the role of the E-cadherin/catenin complex proteins under more physiological three-dimensional (3D) cell culture conditions in a panel of CRC cell lines. In contrast to floating spheroids and growth in the laminin-rich matrix, collagen type 1 induced the formation of two distinct growth phenotypes, i.e., cell groups and single cells, in 5 out of the 8 CRC cell lines. Further characterization of these subpopulations revealed that, intriguingly, cell-cell contact proteins are important for invasion, but negligible for radiochemosensitivity, proliferation and adhesion. Despite the generation of genomic and transcriptomic data, we were unable to elucidate the mechanisms through which α-catenin affects collagen type 1 invasion. In a retrospective analysis of patients with rectal carcinoma, a low α-catenin expression trended with overall survival, as well as locoregional and distant control. Our results suggest that the E-cadherin/catenin complex proteins forming cell-cell contacts are mainly involved in the invasion, rather than the radiochemosensitivity of 3D grown CRC cells. Further studies are warranted in order to provide a better understanding of the molecular mechanisms controlling cell-cell adhesion in the context of radiochemoresistance.

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Section: Resultssupporting

confidence: 79%

“…In line with other studies ( 26 , 28 , 29 ), we isolated, propagated and characterized the two distinct DLD-1 subpopulations. The DLD-1 subpopulations grew either as compact cell clusters or as groups of single cells in 3D col-I ( Fig.…”

Section: Resultssupporting

confidence: 61%

Differential effects of α-catenin on the invasion and radiochemosensitivity of human colorectal cancer cells

et al. 2018

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“…Despite its critical role in cancer progression, the mechanism behind α-catenin downregulation is unclear. Some reports have suggested that DNA methylation, genetic alterations, and hypoxia in the cancer microenvironment play a role 4,23,27,28. Here, we provided novel insights into the regulation of α-catenin in CRC by focusing on the innate immune component NF-κB signaling.…”

Section: Discussionmentioning

confidence: 88%

Lipopolysaccharide-induced α-catenin downregulation enhances the motility of human colorectal cancer cells in an NF-κB signaling-dependent manner

Cheng

Yang

et al. 2016

OTT

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α-Catenin is an important molecule involved in the maintenance of cell–cell adhesion and a prognostic marker in cancer since its expression is essential for preventing cancer metastasis. However, the mechanism that leads to the downregulation of α-catenin in cancer progression remains unclear. The present study revealed that lipopolysaccharide (LPS)-induced NF-κB signaling activation suppressed α-catenin expression and motility in SW620 colorectal cancer (CRC) cells, using real-time polymerase chain reaction, Western blotting, and transwell migration assays. LPS treatment reduced both the mRNA and protein expression of α-catenin and thereby enhanced cell motility. Conversely, incubating cells with an NF-κB inhibitor disrupted these effects. Furthermore, the ectopic expression of p65 alone mimicked the effects of LPS stimulation. In CRC tissues, the presence of enteric bacterial LPS-related neutrophil-enriched foci was correlated with α-catenin downregulation. Collectively, these findings suggest that LPS-induced NF-κB signaling is related to α-catenin suppression and enhanced cell motility in CRC. Therefore, NF-κB is a novel potential therapeutic target for CRC metastasis.

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“…Absent or reduced ␣-catenin expression increases tumorigenic characteristics in vitro (37) and has been documented in esophageal, lung, stomach, pancreatic, and colorectal cancers (36,38,50). It has also been associated with metastasis (10,11).…”

Section: Discussionmentioning

confidence: 99%

DLC1 Interaction with α-Catenin Stabilizes Adherens Junctions and Enhances DLC1 Antioncogenic Activity

Tripathi

Popescu

Zimonjic

2012

Molecular and Cellular Biology

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The DLC1 (for deleted in liver cancer 1) tumor suppressor gene encodes a RhoGAP protein that inactivates Rho GTPases, which are implicated in regulation of the cytoskeleton and adherens junctions (AJs), a cell-cell adhesion protein complex associated with the actin cytoskeleton. Malignant transformation and tumor progression to metastasis are often associated with changes in cytoskeletal organization and cell-cell adhesion. Here we have established in human cells that the AJ-associated protein ␣-catenin is a new binding partner of DLC1. Their binding was mediated by the N-terminal amino acids 340 to 435 of DLC1 and the N-terminal amino acids 117 to 161 of ␣-catenin. These proteins colocalized in the cytosol and in the plasma membrane, where together they associated with E-cadherin and ␤-catenin, constitutive AJ proteins. Binding of DLC1 to ␣-catenin led to their accumulation at the plasma membrane and required DLC1 GAP activity. Knocking down ␣-catenin in DLC1-positive cells diminished DLC1 localization at the membrane. The DLC1-␣-catenin complex reduced the Rho GTP level at the plasma membrane, increased E-cadherin's mobility, affected actin organization, and stabilized AJs. This process eventually contributed to a robust oncosuppressive effect of DLC1 in metastatic prostate carcinoma cells. Together, these results unravel a new mechanism through which DLC1 exerts its strong oncosuppressive function by positively influencing AJ stability. Cancer initiation and progression constitute a multistep process, associated with both structural changes in certain genes and alterations in the dynamics and magnitude of their expression. Mutations and various chromosome rearrangements can invariably change the nature of the gene-encoded message; different molecular interactions and epigenetic modifications can modulate gene expression. Accumulation of genetic and epigenetic abnormalities results in the appearance of deviant cells refractory to normal homeostatic regulatory mechanisms and with a newly acquired capacity for unlimited, self-sufficient proliferation (6,20).Activation of oncogenes and/or inactivation of tumor suppressor genes (TSG) is often associated with a neoplastic phenotype. Over the past few years, the DLC1 gene, encoding a Rho GTPaseactivating protein (RhoGAP), has been established as a genuine TSG and increasingly considered a metastasis suppressor gene in various cancers. Aberrant upregulation of Rho GTPases is a major factor in the neoplastic process and tumor progression to metastasis (13). DLC1 plays a key role in regulation of actin cytoskeleton and focal adhesions, in the process of cell migration and invasion, tumor cell dissemination, and metastasis, and in programmed cell death and neoangiogenesis (13,16,19,26,39,49,64,69). DLC1 has been shown to be one of the most frequently inactivated TSGs, predominantly by epigenetic modifications (13,29,30,58,60,66). Restoration of DLC1 expression in various carcinomas and in multiple myeloma cell lines results in suppression of proliferation, tumorigenicit...

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Modulation of the Tumor Suppressor Protein α-Catenin by Ischemic Microenvironment

Cited by 8 publications

References 57 publications

Differential effects of α-catenin on the invasion and radiochemosensitivity of human colorectal cancer cells

Differential effects of α-catenin on the invasion and radiochemosensitivity of human colorectal cancer cells

Lipopolysaccharide-induced α-catenin downregulation enhances the motility of human colorectal cancer cells in an NF-κB signaling-dependent manner

DLC1 Interaction with α-Catenin Stabilizes Adherens Junctions and Enhances DLC1 Antioncogenic Activity

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Modulation of the Tumor Suppressor Protein α-Catenin by Ischemic Microenvironment

Cited by 8 publications

References 57 publications

Differential effects of α-catenin on the invasion and radiochemosensitivity of human colorectal cancer cells

Differential effects of α-catenin on the invasion and radiochemosensitivity of human colorectal cancer cells

Lipopolysaccharide-induced &alpha;-catenin downregulation enhances the motility of human colorectal cancer cells in an NF-&kappa;B signaling-dependent manner

DLC1 Interaction with α-Catenin Stabilizes Adherens Junctions and Enhances DLC1 Antioncogenic Activity

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Lipopolysaccharide-induced α-catenin downregulation enhances the motility of human colorectal cancer cells in an NF-κB signaling-dependent manner