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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wnt-targeted gene therapy has been proposed as a treatment for human colorectal cancer (CRC). The Cre-Lox system consists of methodology for enhancing targeted expression from tissue-specific or cancer-specific promoters. We analyzed the efficiency of Wnt-specific promoters as drivers of the Cre-mediated activity of a luciferase reporter gene or cell death effector gene in CRC cell lines in the presence and absence of two modulators of Wnt activity, sodium butyrate and lithium chloride. Butyrate is present in the colonic lumen after digestion of fiber-rich foods, whereas the colonic lumen is readily accessible to lithium chloride. In both SW620 and HCT-116 CRC cells, a physiologically relevant concentration of butyrate upregulated reporter and effector activity and altered the Wnt-specific expression pattern. Lithium chloride markedly enhanced Cre-Lox-mediated Wnt-specific reporter expression only in APC wild-type CRC cells. Possibilities for genetic modulation of the proposed CRC therapy included Wnt-specific expression of a floxed Lef1-VP16 fusion that enhanced Wnt-specific cell death and of a floxed dominant-negative Tcf4 that specifically downregulated endogenous Wnt activity. These findings demonstrated that the Cre-Lox system, in combination with pharmacological and genetic modulators, represents effective methodology for enhancing Wnt-targeted gene therapy.
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PMID:Pharmacological and genetic modulation of Wnt-targeted Cre-Lox-mediated gene expression in colorectal cancer cells. 1514 Oct 37

Butyrate, a product of dietary fiber and a histone deacetylase inhibitor, induces apoptosis of colorectal cancer cells; this effect of butyrate is in part mediated by its ability to hyperactivate Wnt signaling, and may in part explain the preventive action of dietary fiber against colorectal cancer. However, the mechanisms by which Wnt hyperactivation promotes apoptosis are unknown. Inactivation of the retinoblastoma tumor suppressor occurs in some cancers and can lead to context-dependent cell proliferation or cell death/apoptosis. The function of retinoblastoma protein (Rb) in normal cells is modulation of cell cycle; inactivation of Rb allows for cell cycle progression and, hence, cell proliferation. Wnt signaling is upregulated in a variety of cancers, and deregulated Wnt signaling is a key initiating event in most cases of sporadic colorectal cancer. It has been shown that Wnt signaling activated by APC inactivation can synergize with the inactivation of Rb to induce apoptosis in a manner mediated by increased TORC1 activity, leading to induced metabolic and energy stress. Rb is typically not inactivated in colorectal cancer; however, Rb is phosphorylated and deactivated during cell cycle G1/S transition. This manuscript posits that it is during this time that butyrate/histone deacetylase inhibitor-induced Wnt hyperactivation induces apoptosis in colorectal cancer cells. Thus, the inactivation of Rb in cell cycle progression may synergize with Wnt hyperactivation to induce apoptosis in response to histone deacetylase inhibitors. The hypothesis is that hyperactivation of Wnt signaling enhances colorectal cancer cell apoptosis via the interaction between upregulated Wnt signaling and inactivated Rb during cell cycle progression. This paper discusses this hypothesis and offers initial experimental approaches for testing the hypothesis. A better understanding of how histone deacetylase inhibitors induce colorectal cancer cell apoptosis through hyperactivation of Wnt signaling, and of cross-talk between repression of cell cycle and induction of apoptosis that occurs with treatment with histone deacetylase inhibitors, can assist in the development of novel therapies for colorectal cancer.
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PMID:Hypothesis: Retinoblastoma protein inactivation mediates effects of histone deacetylase inhibitor-induced Wnt hyperactivation in colorectal cancer cells. 3194 90