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Within the growing field of amino acid metabolism, tryptophan (Trp) catabolism is an area of increasing interest. Trp is essential for protein synthesis, and its metabolism gives rise to biologically active catabolites including serotonin and numerous metabolites in the kynurenine (Kyn) pathway. In normal tissues, the production of Trp metabolites is directly regulated by the tissue‐specific expression of Trp‐metabolizing enzymes. Alterations of these enzymes in cancers can shift the balance and lead to an increased production of specific byproducts that can function as oncometabolites. For example, increased expression of the enzyme indoleamine 2,3‐dioxygenase, which converts Trp into Kyn, leads to an increase in Kyn levels in numerous cancers. Kyn functions as an oncometabolite in cancer cells by promoting the activity of the transcription factor aryl hydrocarbon receptor, which regulates progrowth genes. Moreover, Kyn also inhibits T‐cell activity and thus allows cancer cells to evade clearance by the immune system. Therefore, targeting the Kyn pathway has become a therapeutic focus as a novel means to abrogate tumor growth and immune resistance. This review summarizes the biological role and regulation of Trp metabolism and its catabolites with an emphasis on tumor cell growth and immune evasion and outlines areas for future research focus. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2010.06.037 Byline: Maralice Conacci-Sorrell (1), Celine Ngouenet (1), Robert N. Eisenman (1) Keywords: CELLBIO; PROTEINS Abstract: The Myc oncoprotein family comprises transcription factors that control multiple cellular functions and are widely involved in oncogenesis. Here we report the identification of Myc-nick, a cytoplasmic form of Myc generated by calpain-dependent proteolysis at lysine 298 of full-length Myc. Myc-nick retains conserved Myc box regions but lacks nuclear localization signals and the bHLHZ domain essential for heterodimerization with Max and DNA binding. Myc-nick induces [alpha]-tubulin acetylation and altered cell morphology by recruiting histone acetyltransferase GCN5 to microtubules. During muscle differentiation, while the levels of full-length Myc diminish, Myc-nick and acetylated [alpha]-tubulin levels are increased. Ectopic expression of Myc-nick accelerates myoblast fusion, triggers the expression of myogenic markers, and permits Myc-deficient fibroblasts to transdifferentiate in response to MyoD. We propose that the cleavage of Myc by calpain abrogates the transcriptional inhibition of differentiation by full-length Myc and generates Myc-nick, a driver of cytoplasmic reorganization and differentiation. Author Affiliation: (1) Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA Article History: Received 9 November 2009; Revised 2 March 2010; Accepted 18 May 2010 Article Note: (miscellaneous) Published: August 5, 2010

The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) regulates cellular detoxification, proliferation and immune evasion in a range of cell types and tissues, including cancer cells. In this study, we used RNA-sequencing to identify the signature of the AHR target genes regulated by the pollutant 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and the endogenous ligand kynurenine (Kyn), a tryptophan-derived metabolite. This approach identified a signature of six genes (CYP1A1, ALDH1A3, ABCG2, ADGRF1 and SCIN) as commonly activated by endogenous or exogenous ligands of AHR in multiple colon cancer cell lines. Among these, the actin-severing protein scinderin (SCIN) was necessary for cell proliferation; SCIN downregulation limited cell proliferation and its expression increased it. SCIN expression was elevated in a subset of colon cancer patient samples, which also contained elevated ß-catenin levels. Remarkably, SCIN expression promoted nuclear translocation of ß-catenin and activates the WNT pathway. Our study identifies a new mechanism for adhesion-mediated signaling in which SCIN, likely via its ability to alter the actin cytoskeleton, facilitates the nuclear translocation of ß-catenin. [ABSTRACT FROM AUTHOR]

Aberrant [beta]-catenin-TCF target gene activation plays a key role in colorectal cancer, both in the initiation stage and during invasion and metastasis. We identified the neuronal cell adhesion molecule L1, as a target gene of [beta]-catenin-TCF signaling in colorectal cancer cells. L1 expression was high in sparse cultures and coregulated with ADAM10, a metalloprotease involved in cleaving and shedding L1's extracellular domain. L1 expression conferred increased cell motility, growth in low serum, transformation and tumorigenesis, whereas its suppression in colon cancer cells decreased motility. L1 was exclusively localized in the invasive front of human colorectal tumors together with ADAM10. The transmembrane localization and shedding of L1 by metalloproteases could be useful for detection and as target for colon cancer therapy.

Transcriptional repression of E-cadherin, characteristic of epithelial to mesenchymal transition, is often found also during tumor cell invasion. At metastases, migratory fibroblasts sometimes revert to an epithelial phenotype, by a process involving regulation of the E-cadherin-[beta]-catenin complex. We investigated the molecular basis of this regulation, using human colon cancer cells with aberrantly activated [beta]-catenin signaling. Sparse cultures mimicked invasive tumor cells, displaying low levels of E-cadherin due to transcriptional repression of E-cadherin by Slug. Slug was induced by [beta]-catenin signaling and, independently, by ERK. Dense cultures resembled a differentiated epithelium with high levels of E-cadherin and [beta]-catenin in adherens junctions. In such cells, [beta]-catenin signaling, ErbB-1/2 levels, and ERK activation were reduced and Slug was undetectable. Disruption of E-cadherin-mediated contacts resulted in nuclear localization and signaling by [beta]-catenin, induction of Slug and inhibition of E-cadherin transcription, without changes in ErbB-1/2 and ERK activation. This autoregulation of E-cadherin by cell-cell adhesion involving Slug, [beta]-catenin and ERK could be important in tumorigenesis.

Research has been conducted on beta-catenin and plakoglobin. The target genes have been identified by these proteins via the use of DNA microarray analysis carried out with RNA from the cells which express these proteins and the results are presented.

Members of the MYC family of proto-oncogenes are the most commonly deregulated genes in all human cancers. MYC proteins drive an increase in cellular proliferation and facilitate multiple aspects of tumor initiation and progression, thereby controlling all hallmarks of cancer. MYC's ability to drive metabolic reprogramming of tumor cells leading to biomass accumulation and cellular proliferation is the most studied function of these oncogenes. MYC also regulates tumor progression and is often implicated in resistance to chemotherapy and in metastasis. While most oncogenic functions of MYC are attributed to its role as a transcription factor, more recently, new roles of MYC as a pro-survival factor in the cytoplasm suggest a previously unappreciated diversity in MYC's roles in cancer progression. This review will focus on the role of MYC in invasion and will discuss the canonical functions of MYC in Epithelial to Mesenchymal Transition and the cytoplasmic functions of MYC-nick in collective migration [ABSTRACT FROM AUTHOR]