{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:23:53Z","timestamp":1791260633313,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background and Objectives: Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide. Although chemotherapy is an effective treatment for colorectal cancer (CRC), its effectiveness is frequently hindered by the emergence of resistant cancer cells. Studies have demonstrated a linkage between drug resistance and the pregnane X receptor (PXR), which influences the metabolism and the transport of chemotherapeutic agents. Likewise, autophagy is also a well-established mechanism that contributes to chemotherapy resistance, and it is closely tied to tumor progression. This pre-clinical study aims to investigate the role of mtKRAS-dependent autophagy with PXR expression after treatment with Irinotecan in colorectal cancer. Methods: CRC lines were treated with specific inhibitors, such as 3-methyladeninee, hydroxychloroquine PI-103, and irinotecan hydrochloride, and subjected to various assays, including MTT for cell viability, Western blot for protein expression, siRNA-mediated PXR knock-out, and confocal microscopy for autophagic vacuole visualization. Protein quantification, gene knockdown, and subcellular localization studies were performed under standardized conditions to investigate treatment effects on autophagy and apoptosis pathways. Conclusions: Our experiments showed that PXR knockdown does not alter autophagy levels following Irinotecan treatment, but it promotes apoptotic cell death despite elevated autophagy. Moreover, late-stage autophagy inhibition reduces PXR expression, whereas induction through PI3K\/AKT\/mTOR inhibition leads to increased expression of PXR. Our experiments uncover a mechanism by which autophagy facilitates the nuclear translocation of the PXR, thereby promoting resistance to Irinotecan across multiple cell lines.<\/jats:p>","DOI":"10.3390\/genes16080892","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T14:50:03Z","timestamp":1753714203000},"page":"892","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Autophagy and PXR Crosstalk in the Regulation of Cancer Drug Metabolism and Resistance According to Gene Mutational Status in Colorectal Cancer"],"prefix":"10.3390","volume":"16","author":[{"given":"Evangelos","family":"Koustas","sequence":"first","affiliation":[{"name":"Oncology Department, General Hospital Evangelismos, Ipsilantou 45-47, 106 76 Athens, Greece"},{"name":"First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5848-7905","authenticated-orcid":false,"given":"Panagiotis","family":"Sarantis","sequence":"additional","affiliation":[{"name":"First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece"},{"name":"University Pathology Clinic, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapoditrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0080-9032","authenticated-orcid":false,"given":"Eleni-Myrto","family":"Trifylli","sequence":"additional","affiliation":[{"name":"GI-Liver Unit, 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, General Hospital of Athens \u201cHippocratio\u201d, 114 Vas Sofias, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleftheria","family":"Dikoglou-Tzanetatou","sequence":"additional","affiliation":[{"name":"First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia","family":"Ioakeimidou","sequence":"additional","affiliation":[{"name":"First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7560-0575","authenticated-orcid":false,"given":"Ioanna A.","family":"Anastasiou","sequence":"additional","affiliation":[{"name":"Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 115 27 Athens, Greece"},{"name":"Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1369-8201","authenticated-orcid":false,"given":"Michalis V.","family":"Karamouzis","sequence":"additional","affiliation":[{"name":"University Pathology Clinic, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapoditrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stamatios","family":"Theocharis","sequence":"additional","affiliation":[{"name":"First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Roshandel, G., Ghasemi-Kebria, F., and Malekzadeh, R. 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