New perspectives on APC control of cell fate and proliferation in colorectal cancer

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 09/2009; 8(16):2549-56. DOI: 10.4161/cc.8.16.9278
Source: PubMed


Aberrant Wnt/beta-catenin signaling following loss of the tumor suppressor adenomatous polyposis coli (APC) is thought to initiate colon adenoma formation. Considerable evidence for this model has come from mouse models of Apc truncation where nuclear beta-catenin is detectable soon after loss of Apc. However, examination of tumors from familial adenomatous polyposis coli (FAP) patients has failed to confirm the presence of nuclear beta-catenin in early lesions following APC loss despite robust staining in later lesions. This observation presents the possibility that colon adenomas arise through a beta-catenin-independent function of APC. Additionally, there is a well established role for inflammation and specifically COX-2 and prostaglandin E2 in the progression of colorectal cancer. Here we review the current literature regarding the functions of APC in regulating WNT/beta-catenin signaling as well as its control of intestinal cell fate and differentiation. Further, we provide a brief commentary on our current understanding of the role that inflammation plays in colorectal tumorigenesis and how it fits in with APC dysfunction. Though there are currently contrasting models to explain colon tumorigenesis, our goal is to begin to reconcile data from multiple different model systems and provide a functional view into the initiation and progression of colon cancer.

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Available from: Diana M Stafforini, Jun 29, 2015
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    • "APC mutations promote b-catenin translocation to the nucleus (Sansom et al., 2004), although the quantitative extent is modulated by other, poorly understood factors. APC mutated tumors retain membrane b-catenin comparable to normal epithelium in the tumor center, whereas cells at the invasive front show nuclear b-catenin (Brabletz et al., 1998; Phelps et al., 2009). This observation suggests that the effects of mutations are modulated by a dynamic competition between tumor promoting and suppressive forces that may depend on the signaling status of individual cells and their local microenvironment. "
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    ABSTRACT: Self-renewal is essential for multicellular organisms but carries the risk of somatic mutations that can lead to cancer, which is particularly critical for rapidly renewing tissues in a highly mutagenic environment such as the intestinal epithelium. Using computational modeling and in vivo experimentation, we have analyzed how adenomatous polyposis coli (APC) mutations and β-catenin aberrations affect the maintenance of mutant cells in colonic crypts. The increasing abundance of APC along the crypt axis forms a gradient of cellular adhesion that causes more proliferative cells to accelerate their movement toward the top of the crypt, where they are shed into the lumen. Thus, the normal crypt can efficiently eliminate β-catenin mutant cells, whereas APC mutations favor retention. Together, the molecular design of the APC/β-catenin signaling network integrates cell proliferation and migration dynamics to translate intracellular signal processing and protein gradients along the crypt into intercellular interactions and whole-crypt physiological or pathological behavior.
    Full-text · Article · Mar 2014 · Cell Reports
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    • "These observations have also raised the possibility that additional effectors downstream of APC might contribute to Apc loss-offunction phenotypes (Phelps et al., 2009a; Phelps et al., 2009b). APC has Wnt/β-catenin-independent roles, including regulation of apoptosis, microtubule dynamics, regulation of retinoic acid biosynthesis and cell-cell adhesion (Hanson and Miller, 2005; Phelps et al., 2009a). We previously found that APC directly enhances the activity of glycogen synthase kinase-3 (GSK-3) (Valvezan et al., 2012). "
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    ABSTRACT: Truncating mutations in Apc are strongly linked to colorectal cancers. APC is a negative regulator of the Wnt pathway and constitutive Wnt activation mediated by enhanced Wnt/β-catenin target gene activation is believed to be the predominant mechanism responsible for Apc mutant phenotypes. However, recent evidence suggests that additional downstream effectors contribute to Apc mutant phenotypes. We previously identified a mechanism by which APC, acting through GSK-3, suppresses mTORC1, a nutrient sensor that regulates cell growth and proliferation. We hypothesized that truncating Apc mutations should activate mTORC1 in vivo and that mTORC1 plays an important role in Apc mutant phenotypes. We find mTORC1 is strongly activated in Apc mutant zebrafish and in intestinal polyps in Apc mutant mice. Furthermore, mTORC1 activation is essential downstream of APC as mTORC1 inhibition partially rescues Apc mutant phenotypes including early lethality, reduced circulation, and liver hyperplasia. Importantly, combining mTORC1 and Wnt inhibition rescues defects in morphogenesis of the anterior-posterior axis that are not rescued by inhibition of either pathway alone. These data establish mTORC1 as a critical, β-catenin independent effector of oncogenic Apc mutations and highlight the importance of mTORC1 regulation by APC during embryonic development. Our findings also suggest a new model of colorectal cancer pathogenesis in which mTORC1 is activated in parallel with Wnt/β-catenin signaling.
    Full-text · Article · Oct 2013 · Disease Models and Mechanisms
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    • "Without stimulation by Wnt, β-catenin is assembled into the so-called destruction complex, in which APC protein plays a central role, and includes Axin, GSK3β, and Casein kinase 1 (CK1). This complex directs a series of phosphorylation events in β-catenin that targets it for ubiquitination and subsequent proteolysis via the proteosome [5], [6]. Stimulation by Wnt leads to inhibition of β-catenin breakdown, allowing β-catenin to accumulate, enter the nucleus, and activate a Wnt target gene program [5], [7]. "
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    ABSTRACT: The tumor suppressor Adenomatous Polyposis coli (APC) gene is mutated or lost in most colon cancers. Alterations in Protein kinase C (PKC) isozyme expression and aberrant regulation also comprise early events in intestinal carcinomas. Here we show that PKCδ expression levels are decreased in colon tumor cell lines with respect to non-malignant cells. Reciprocal co-immunoprecipitation and immunofluorescence studies revealed that PKCδ interacts specifically with both full-length (from non-malignant cells) and truncated APC protein (from cancerous cells) at the cytoplasm and at the cell nucleus. Selective inhibition of PKCδ in cancer SW480 cells, which do not possess a functional β-catenin destruction complex, did not affect β-catenin-mediated transcriptional activity. However, in human colon carcinoma RKO cells, which have a normal β-catenin destruction complex, negatively affected β-catenin-mediated transcriptional activity, cell proliferation, and the expression of Wnt target genes C-MYC and CYCLIN D1. These negative effects were confirmed by siRNA-mediated knockdown of PKCδ and by the expression of a dominant negative form of PKCδ in RKO cells. Remarkably, the PKCδ stably depleted cells exhibited augmented tumorigenic activity in grafted mice. We show that PKCδ functions in a mechanism that involves regulation of β-catenin degradation, because PKCδ inhibition induces β-catenin stabilization at the cytoplasm and its nuclear presence at the C-MYC enhancer even without Wnt3a stimulation. In addition, expression of a dominant form of PKCδ diminished APC phosphorylation in intact cells, suggesting that PKCδ may modulate canonical Wnt activation negatively through APC phosphorylation.
    Full-text · Article · Mar 2013 · PLoS ONE
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