{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:13:40Z","timestamp":1789470820249,"version":"build-2803163510"},"reference-count":76,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan","doi-asserted-by":"publisher","award":["JP21H03356"],"award-info":[{"award-number":["JP21H03356"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Epidemiological studies suggest an increased risk of colorectal cancer (CRC) aggravation in patients with chronic kidney disease (CKD). Our previous study demonstrated that indoxyl sulfate, a uremic toxin whose concentration increases with CKD progression, exacerbates CRC through activation of the AhR and Akt pathways. Consequently, indoxyl sulfate has been proposed to be a significant link between CKD progression and CRC aggravation. The present study aimed to investigate the roles of c-Myc and \u03b2-Catenin, which are hypothesized to be downstream factors of indoxyl sulfate-induced AhR and Akt activation, in CRC cell proliferation and EGF sensitivity in HCT-116 CRC cells. Indoxyl sulfate significantly induced CRC cell proliferation at concentrations exceeding 62.5 \u00b5M, a process suppressed by the c-Myc inhibitor 10058-F4. Indoxyl sulfate activated the Akt\/\u03b2-Catenin\/c-Myc pathway as evidenced by the Akt inhibitor MK2206, which decreased both \u03b2-Catenin and c-Myc protein levels, and the \u03b2-Catenin inhibitor XAV-939, which reduced c-Myc protein levels. The AhR antagonist CH223191 also inhibited c-Myc upregulation, indicating involvement of the AhR\/c-Myc pathway. MK2206 partially attenuated the indoxyl sulfate-induced AhR transcriptional activity, suggesting that Akt activation influences the AhR\/c-Myc pathway. MK2206, CH223191, and 10058-F4 suppressed the increase in EGFR protein levels induced by indoxyl sulfate, indicating that the Akt\/\u03b2-Catenin\/c-Myc and AhR\/c-Myc pathways enhance the sensitivity of HCT-116 CRC cells to EGF. These findings indicate that the elevation of indoxyl sulfate levels in the blood, due to CKD progression, could worsen CRC by promoting the proliferation of CRC cells and enhancing EGF signaling. Therefore, indoxyl sulfate could potentially serve as a therapeutic target for CRC aggravation in patients with CKD.<\/jats:p>","DOI":"10.3390\/toxins17010017","type":"journal-article","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T11:24:19Z","timestamp":1735730659000},"page":"17","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The Role of Indoxyl Sulfate in Exacerbating Colorectal Cancer During Chronic Kidney Disease Progression: Insights into the Akt\/\u03b2-Catenin\/c-Myc and AhR\/c-Myc Pathways in HCT-116 Colorectal Cancer Cells"],"prefix":"10.3390","volume":"17","author":[{"given":"Yu","family":"Ichisaka","sequence":"first","affiliation":[{"name":"Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-cho, Matsue 690-8504, Shimane, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Takei","sequence":"additional","affiliation":[{"name":"Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-cho, Matsue 690-8504, Shimane, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuma","family":"Naito","sequence":"additional","affiliation":[{"name":"Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-cho, Matsue 690-8504, Shimane, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manami","family":"Higa","sequence":"additional","affiliation":[{"name":"Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-cho, Matsue 690-8504, Shimane, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9210-2949","authenticated-orcid":false,"given":"Shozo","family":"Yano","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Shimane, Japan"},{"name":"The Center for Integrated Kidney Research and Advance, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Shimane, Japan"},{"name":"Center for Community-Based Health-Care Research and Education (CoHRE), Head Office for Research and Academic Information, Shimane University, 223-8 Enya-cho, Izumo 693-8501, Shimane, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshimitsu","family":"Niwa","sequence":"additional","affiliation":[{"name":"Shubun University, 6 Nikko-cho, Ichinomiya 491-0938, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0939-0098","authenticated-orcid":false,"given":"Hidehisa","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-cho, Matsue 690-8504, Shimane, Japan"},{"name":"The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Tottori, Japan"},{"name":"Faculty of Life and Environmental Sciences, Shimane University, 1060 Nishikawatsu-cho, Matsue 690-8504, Shimane, Japan"},{"name":"Estuary Research Center, Shimane University, 1060 Nishikawatsu-cho, Matsue 690-8504, Shimane, Japan"},{"name":"Interdisciplinary Center for Science Research, Shimane University, 1060 Nishikawatsu-cho, Matsue 690-8504, Shimane, Japan"},{"name":"Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-cho, Matsue 690-8504, Shimane, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1146\/annurev-physiol-031620-091656","article-title":"Function of Renal Nerves in Kidney Physiology and Pathophysiology","volume":"83","author":"Osborn","year":"2021","journal-title":"Annu. 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