Mutation and Expression of the beta-Catenin-interacting Protein ICAT in Human Colorectal Tumors

Cancer cells often acquire capabilities to evade cell death induced by current chemotherapeutic treatment approaches. Caspase-8, a central initiator of death receptor–mediated apoptosis, for example, is frequently inactivated in human cancers via multiple mechanisms such as mutation. Here, we show an approach to overcome cell death resistance in caspase-8–deficient colorectal cancer (CRC) by induction of necroptosis. In both a hereditary and a xenograft mouse model of caspase-8–deficient CRC, second mitochondria-derived activator of caspase (SMAC) mimetic treatment induced massive cell death and led to regression of tumors. We further demonstrate that receptor-interacting protein kinase 3 (RIP3), which is highly expressed in mouse models of CRC and in a subset of human CRC cell lines, is the deciding factor of cancer cell susceptibility to SMAC mimetic–induced necroptosis. Thus, our data implicate that it may be worthwhile to selectively evaluate the efficacy of SMAC mimetic treatment in CRC patients with caspase-8 deficiency in clinical trials for the development of more effective personalized therapy.

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Abstract 4005: The human Norrin/beta-catenin signaling enhancer TSPAN12 is expressed on colorectal tumors; evidence for cell-type specific responsiveness to Norrin signaling in the tumor microenvironment.

10.1158/1538-7445.am2013-4005 ◽

2013 ◽

Author(s):

Kestutis Planutis ◽

Marina Planutiene ◽

Randall F. Holcombe

Keyword(s):

Tumor Microenvironment ◽

Beta Catenin ◽

Colorectal Tumors ◽

Cell Type ◽

Cell Type Specific

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Clinicopathological significance of expression of p-c-Jun, TCF4 and beta-Catenin in colorectal tumors

BMC Cancer ◽

10.1186/1471-2407-8-328 ◽

2008 ◽

Vol 8 (1) ◽

Cited By ~ 9

Author(s):

Kayoko Takeda ◽

Ichiro Kinoshita ◽

Yasushi Shimizu ◽

Yusuke Ohba ◽

Tomoo Itoh ◽

...

Keyword(s):

Beta Catenin ◽

Colorectal Tumors ◽

Clinicopathological Significance

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Histopathologic Features of Colorectal Adenoma and Adenocarcinoma Developing Within Inflammatory Polyps in Miniature Dachshunds

Veterinary Pathology ◽

10.1177/0300985818777798 ◽

2018 ◽

Vol 55 (5) ◽

pp. 654-662 ◽

Cited By ~ 5

Author(s):

Tsubasa Saito ◽

James K. Chambers ◽

Ko Nakashima ◽

Eri Uchida ◽

Koichi Ohno ◽

...

Keyword(s):

Epithelial Cells ◽

Progressive Disease ◽

Tumor Development ◽

Colorectal Polyps ◽

Beta Catenin ◽

Colorectal Tumors ◽

Polyposis Coli ◽

Inflammatory Polyp ◽

Cytokeratin 5 ◽

Initial Biopsy

Biopsy samples of colorectal polyps were collected and examined from 67 Miniature Dachshund dogs (including 35 cases with an additional biopsy). Histopathologic diagnoses of the initial biopsy samples were “inflammatory polyp” in 52 cases (78%), “adenoma” in 10 cases (15%), and “adenocarcinoma” in 5 cases (8%). Eight of 10 cases (80%) diagnosed as adenoma also had inflammatory polyp lesions in the same specimen. A second biopsy was performed in 25 cases (48%) initially diagnosed with inflammatory polyp. Pathologic diagnoses for the second biopsy were inflammatory polyp in 11 cases (44%), adenoma in 9 cases (36%), and adenocarcinoma in 5 cases (20%). The number of beta-catenin-positive nuclei in epithelial cells was significantly higher in adenoma (46%) and adenocarcinoma (75%) as compared with inflammatory polyp (6%). Normal epithelial cells and hyperplastic goblet cells in inflammatory polyps showed homogeneous positive cytoplasmic immunoreactivity for adenomatous polyposis coli (APC) antigen. However, APC expression was decreased in areas of intense nuclear beta-catenin expression in adenoma and adenocarcinoma lesions. Foci of cytokeratin 5/6–positive squamous cell-like neoplastic cells showed intense beta-catenin nuclear expression that was similar to squamous morules described in human colorectal tumors. The results of the present study suggest that the inflammatory polyp in Miniature Dachshunds is a progressive disease that may develop into adenoma and/or adenocarcinoma. In addition, immunohistochemical findings suggest that aberrations of APC and beta-catenin expression may be involved in tumor development within the inflammatory polyp lesions.

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Early signalling events of autophagy

Essays in Biochemistry ◽

10.1042/bse0550001 ◽

2013 ◽

Vol 55 ◽

pp. 1-15 ◽

Cited By ~ 16

Author(s):

Laura E. Gallagher ◽

Edmond Y.W. Chan

Keyword(s):

Protein Kinase ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Mammalian Cells ◽

Mammalian Target Of Rapamycin ◽

Interacting Protein ◽

The Core ◽

Autophagy Gene ◽

Autophagy Induction ◽

Cellular Pathways

Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1–ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1–ULK1 signalling module.

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Functional amyloid: widespread in Nature, diverse in purpose

Essays in Biochemistry ◽

10.1042/bse0560207 ◽

2014 ◽

Vol 56 ◽

pp. 207-219 ◽

Cited By ~ 77

Author(s):

Chi L.L. Pham ◽

Ann H. Kwan ◽

Margaret Sunde

Keyword(s):

Spider Silk ◽

Epigenetic Inheritance ◽

Fibrillar Structure ◽

Cytoplasmic Polyadenylation ◽

Functional Amyloid ◽

Interacting Protein ◽

Diverse Range ◽

Element Binding Protein ◽

Functional Amyloids ◽

Micro Organisms

Amyloids are insoluble fibrillar protein deposits with an underlying cross-β structure initially discovered in the context of human diseases. However, it is now clear that the same fibrillar structure is used by many organisms, from bacteria to humans, in order to achieve a diverse range of biological functions. These functions include structure and protection (e.g. curli and chorion proteins, and insect and spider silk proteins), aiding interface transitions and cell–cell recognition (e.g. chaplins, rodlins and hydrophobins), protein control and storage (e.g. Microcin E492, modulins and PMEL), and epigenetic inheritance and memory [e.g. Sup35, Ure2p, HET-s and CPEB (cytoplasmic polyadenylation element-binding protein)]. As more examples of functional amyloid come to light, the list of roles associated with functional amyloids has continued to expand. More recently, amyloids have also been implicated in signal transduction [e.g. RIP1/RIP3 (receptor-interacting protein)] and perhaps in host defence [e.g. aDrs (anionic dermaseptin) peptide]. The present chapter discusses in detail functional amyloids that are used in Nature by micro-organisms, non-mammalian animals and mammals, including the biological roles that they play, their molecular composition and how they assemble, as well as the coping strategies that organisms have evolved to avoid the potential toxicity of functional amyloid.

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