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Blocking endothelin-1-receptor/?-catenin circuit sensitizes to chemotherapy in colorectal cancer.

ABSTRACT: The limited clinical response to conventional chemotherapeutics observed in colorectal cancer (CRC) may be related to the connections between the hyperactivated ?-catenin signaling and other pathways in CRC stem-like cells (CRC-SC). Here, we show the mechanistic link between the endothelin-1 (ET-1)/ET-1 receptor (ET-1R) signaling and ?-catenin pathway through the specific interaction with the signal transducer ?-arrestin1 (?-arr1), which initiates signaling cascades as part of the signaling complex. Using a panel of patient-derived CRC-SC, we show that these cells secrete ET-1 and express ET_AR and ?-arr1, and that the activation of ET_AR/?-arr1 axis promotes the cross-talk with ?-catenin signaling to sustain stemness, epithelial-to-mesenchymal transition (EMT) phenotype and response to chemotherapy. Upon ET_AR activation, ?-arr1 acts as a transcription co-activator that binds ?-catenin, thereby promoting nuclear complex with ?-catenin/TFC4 and p300 and histone acetylation, inducing chromatin reorganization on target genes, such as ET-1. The enhanced transcription of ET-1 increases the self-sustained ET-1/?-catenin network. All these findings provide a strong rationale for targeting ET-1R to hamper downstream ?-catenin/ET-1 autocrine circuit. Interestingly, treatment with macitentan, a dual ET_AR and ET_BR antagonist, able to interfere with tumor and microenvironment, disrupts the ET-1R/?-arr1-?-catenin interaction impairing pathways involved in cell survival, EMT, invasion, and enhancing sensitivity to oxaliplatin (OX) and 5-fluorouracil (5-FU). In CRC-SC xenografts, the combination of macitentan and OX or 5-FU enhances the therapeutic effects of cytotoxic drugs. Together, these results provide mechanistic insight into how ET-1R coopts ?-catenin signaling and offer a novel therapeutic strategy to manage CRC based on the combination of macitentan and chemotherapy that might benefit patients whose tumors show high ET_AR and ?-catenin expression.

SUBMITTER: Cianfrocca R

PROVIDER: S-EPMC5596423 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Blocking endothelin-1-receptor/β-catenin circuit sensitizes to chemotherapy in colorectal cancer.

Cianfrocca Roberta R Rosanò Laura L Tocci Piera P Sestito Rosanna R Caprara Valentina V Di Castro Valeriana V De Maria Ruggero R Bagnato Anna A

Cell death and differentiation 20170714 10

The limited clinical response to conventional chemotherapeutics observed in colorectal cancer (CRC) may be related to the connections between the hyperactivated β-catenin signaling and other pathways in CRC stem-like cells (CRC-SC). Here, we show the mechanistic link between the endothelin-1 (ET-1)/ET-1 receptor (ET-1R) signaling and β-catenin pathway through the specific interaction with the signal transducer β-arrestin1 (β-arr1), which initiates signaling cascades as part of the signaling comp ...[more]

PMID: 28708138

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Project description:DNA damage, induced by either chemical carcinogens or environmental pollutants, plays an important role in the initiation of colorectal cancer. DNA repair processes, however, are involved in both protecting against cancer formation, and also contributing to cancer development, by ensuring genomic integrity and promoting the efficient DNA repair in tumor cells, respectively. Although DNA repair pathways have been well exploited in the treatment of breast and ovarian cancers, the role of DNA repair processes and their therapeutic efficacy in colorectal cancer is yet to be appreciably explored. To understand the role of DNA repair, especially homologous recombination (HR), in chemical carcinogen-induced colorectal cancer growth, we unraveled the role of RAD51AP1 (RAD51-associated protein 1), a protein involved in HR, in genotoxic carcinogen (azoxymethane, AOM)-induced colorectal cancer. Although AOM treatment alone significantly increased RAD51AP1 expression, the combination of AOM and dextran sulfate sodium (DSS) treatment dramatically increased by several folds. RAD51AP1 expression is found in mouse colonic crypt and proliferating cells. RAD51AP1 expression is significantly increased in majority of human colorectal cancer tissues, including BRAF/KRAS mutant colorectal cancer, and associated with reduced treatment response and poor prognosis. Rad51ap1-deficient mice were protected against AOM/DSS-induced colorectal cancer. These observations were recapitulated in a genetically engineered mouse model of colorectal cancer (ApcMin /+ ). Furthermore, chemotherapy-resistant colorectal cancer is associated with increased RAD51AP1 expression. This phenomenon is associated with reduced cell proliferation and colorectal cancer stem cell (CRCSC) self-renewal. Overall, our studies provide evidence that RAD51AP1 could be a novel diagnostic marker for colorectal cancer and a potential therapeutic target for colorectal cancer prevention and treatment. IMPLICATIONS: This study provides first in vivo evidence that RAD51AP1 plays a critical role in colorectal cancer growth and drug resistance by regulating CRCSC self-renewal.

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Blocking endothelin-1-receptor/?-catenin circuit sensitizes to chemotherapy in colorectal cancer.

Publications

Blocking endothelin-1-receptor/β-catenin circuit sensitizes to chemotherapy in colorectal cancer.

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