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Suppression of colon carcinogenesis by targeting Notch signaling.

ABSTRACT: Recent studies have shown that aberrant Notch signaling contributes to the pathogenesis of colorectal cancer (CRC). However, the potential therapeutic benefits of Notch pathway inhibitors, including gamma-secretase inhibitors (GSIs) on colon carcinogenesis are still unclear. In this study, the effects of the GSI, N-[N-3,5-difluorophenacetyl]-L-alanyl-S-phenylglycine methyl ester (DAPM) on colon carcinogenesis were investigated. In vitro, DAPM suppressed cell proliferation and induced the expression of Krüppel-like factor 4 (KLF4) and p21 in human colon cancer cells. Interestingly, p21-null HCT 116 cells were largely resistant to the suppressive effects of DAPM on cell proliferation compared with the parental cells. To investigate the effects of DAPM in vivo, colonoscopy was performed to establish the presence of colon tumors 9 weeks after azoxymethane treatment. After tumors were identified, mice were injected intraperitoneally every other day with either DAPM or vehicle for 4 weeks. The frequency of both large (>4mm) and small (<1mm) colon tumors was significantly reduced by DAPM treatment. Colon tumors in the DAPM-treated mice displayed increased levels of KLF4 and p21, accompanied by reduced Ki-67 staining compared with controls. Notably, in human colon tumor biopsies, KLF4 and p21 expressions were present within hyperplastic polyps, but the levels of both proteins were markedly reduced in tubular adenomas. Our results suggest that inhibition of Notch signaling by DAPM provides a potential chemopreventive strategy for patients with tubular adenomas, in part via activation of the KLF4-p21 axis.

SUBMITTER: Miyamoto S

PROVIDER: S-EPMC3786381 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Suppression of colon carcinogenesis by targeting Notch signaling.

Miyamoto Shingo S Nakanishi Masako M Rosenberg Daniel W DW

Carcinogenesis 20130601 10

Recent studies have shown that aberrant Notch signaling contributes to the pathogenesis of colorectal cancer (CRC). However, the potential therapeutic benefits of Notch pathway inhibitors, including gamma-secretase inhibitors (GSIs) on colon carcinogenesis are still unclear. In this study, the effects of the GSI, N-[N-3,5-difluorophenacetyl]-L-alanyl-S-phenylglycine methyl ester (DAPM) on colon carcinogenesis were investigated. In vitro, DAPM suppressed cell proliferation and induced the express ...[more]

PMID: 23729655

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Project description:BackgroundPancreatic cancer is one of the deadliest human malignancies, with few therapeutic options. Re-activation of embryonic signaling pathways is commonly in human pancreatic cancer and provided rationale to explore inhibition of these pathways therapeutically. Notch signaling is important during pancreatic development, and it is re-activated in pancreatic cancer. The functional role of Notch signaling during pancreatic carcinogenesis has been previously characterized using both genetic and drug-based approaches. However, contrasting findings were reported based on the study design. In fact, Notch signaling has been proposed to act as tumor-promoter or tumor-suppressor. Given the availability of Notch inhibitors in the clinic, understanding how this signaling pathway contributes to pancreatic carcinogenesis has important therapeutic implications. Here, we interrogated the role of Notch signaling specifically in the epithelial compartment of the pancreas, in the context of a genetically engineered mouse model of pancreatic cancer.MethodsTo inhibit Notch signaling in the pancreas epithelium, we crossed a mouse model of pancreatic cancer based on pancreas-specific expression of mutant Kras with a transgenic mouse that conditionally expresses a dominant negative form of the Mastermind-like 1 gene. MAML is an essential co-activator of the canonical Notch signaling-mediated transcription. DNMAML encodes a truncated MAML protein that represses all canonical Notch mediated transcription in a cell autonomous manner, independent of which Notch receptor is activated. As a result, in mice co-expressing mutant Kras and DNMAML, Notch signaling is inhibited specifically in the epithelium upon Cre-mediated recombination. We explored the effect of epithelial-specific DNMAML expression on Kras-driven carcinogenesis both during normal aging and following the induction of acute pancreatitis.ResultsWe find that DNMAML expression efficiently inhibits epithelial Notch signaling and delays PanIN formation. However, over time, loss of Notch inhibition allows PanIN formation and progression.ConclusionsEpithelial-specific Notch signaling is important for PanIN initiation. Our findings indicate that PanIN formation can only occur upon loss of epithelial Notch inhibition, thus supporting an essential role of this signaling pathway during pancreatic carcinogenesis.

Project description:BackgroundRecent studies have implicated aberrant Notch signaling in breast cancers. Yet, relatively little is known about the pattern of expression of various components of the Notch pathway, or its mechanism of action. To better understand the role of the Notch pathway in breast cancer, we have undertaken a detailed expression analysis of various Notch receptors, their ligands, and downstream targets at different stages of breast cancer progression.ResultsWe report here that there is a general increase in the expression levels of Notch 1, 2, 4, Jagged1, Jagged2, and Delta-like 4 proteins in breast cancers, with simultaneous upregulation of multiple Notch receptors and ligands in a given cancer tissue. While Notch3 and Delta-like1 were undetectable in normal tissues, moderate to high expression was detected in several cancers. We detected the presence of active, cleaved Notch1, along with downstream targets of the Notch pathway, Hes1/Hes5, in approximately 75% of breast cancers, clearly indicating that in a large proportion of breast cancers Notch signaling is aberrantly activated. Furthermore, we detected cleaved Notch1 and Hes1/5 in early precursors of breast cancers - hyperplasia and ductal carcinoma in situ - suggesting that aberrant Notch activation may be an early event in breast cancer progression. Mechanistically, while constitutively active Notch1 alone failed to transform immortalized breast cells, it synergized with the Ras/MAPK pathway to mediate transformation. This cooperation is reflected in vivo, as a subset of cleaved Notch positive tumors additionally expressed phopsho-Erk1/2 in the nuclei. Such cases exhibited high node positivity, suggesting that Notch-Ras cooperation may lead to poor prognosis.ConclusionsHigh level expression of Notch receptors and ligands, and its increased activation in several breast cancers and early precursors, places Notch signaling as a key player in breast cancer pathogenesis. Its cooperation with the Ras/MAPK pathway in transformation offers combined inhibition of the two pathways as a new modality for breast cancer treatment.

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Suppression of colon carcinogenesis by targeting Notch signaling.

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Suppression of colon carcinogenesis by targeting Notch signaling.

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