{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T18:09:24Z","timestamp":1792951764936,"version":"4.5.0"},"reference-count":31,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["SFB 1039"],"award-info":[{"award-number":["SFB 1039"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"award":["SFB 1039"],"award-info":[{"award-number":["SFB 1039"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ellinore and Herbert Vogel Stiftung"},{"DOI":"10.13039\/501100001674","name":"Leducq Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01czwga19","id-type":"ROR","asserted-by":"publisher"}]},{"name":"DKFZ\/DKTK fellowship"},{"name":"Biomedical Innovation Academy of the Berlin Institute of Health at Charit\u00e9"},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04pz7b180","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal cell carcinoma (RCC), representing approximately 80% of cases globally. Despite improved diagnosis and therapy, treatment of aggressive or metastatic ccRCC remains challenging due to acquisition of primary or secondary resistance. Among the dysregulated signaling mechanisms identified in ccRCC, the mechanistic target of rapamycin (mTOR) and the nuclear factor kappa light-chain enhancer of activated B cells (NF-\u03baB) pathways play central roles in regulating various biological functions such as metabolism, inflammation, tumor growth, and survival. However, the molecular crosstalk between mTOR and NF-\u03baB signaling in ccRCC progression and therapeutic resistance remains poorly understood. Therefore, in our current study, we aimed to investigate the interplay between mTOR and NF-\u03baB signaling in ccRCC. We analyzed tumor tissue samples from human ccRCC patients. For validation of mTOR and NF-\u03baB signaling, we used two human ccRCC cell lines, A498 and 786-O. Using pharmacological inhibitors of mTOR and IKK\/NF-\u03baB signaling, Torin-1 and MLN120B, respectively, we assessed the functional relationship between these two pathways employing immunoblotting, EdU-based immunocytochemistry, and functional assays. Our findings reveal that both mTOR and NF-\u03baB pathways are aberrantly activated in human ccRCC tissues. Phosphorylation of I\u03baB\u03b1, S6, and 4E-BP1 was increased compared with matched adjacent control tissue. In A498 and 786-O cells, pharmacological inhibition of mTOR or IKK\/NF-\u03baB altered key readouts of the reciprocal pathway, including AKT, S6, 4E-BP1, I\u03baB\u03b1 and p65 phosphorylation. Both inhibitors reduced cell number and EdU incorporation, with stronger anti-proliferative effects observed after Torin-1 treatment. Pharmacological inhibition of either pathway altered key readouts of the other pathway, supporting a reciprocal functional association between mTOR- and NF-\u03baB-associated signaling in the ccRCC models analyzed. Our findings support a functional association between mTOR- and NF-\u03baB-associated signaling in the ccRCC models and provide a rationale for further mechanistic studies evaluating combined pathway modulation.<\/jats:p>","DOI":"10.3390\/ijms27177636","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:11:15Z","timestamp":1787731875000},"page":"7636","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Crosstalk Between mTOR and NF-\u03baB Signaling Pathways in Clear Cell Renal Cell Carcinoma"],"prefix":"10.3390","volume":"27","author":[{"given":"Melanie","family":"Glueck","sequence":"first","affiliation":[{"name":"Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5783-088X","authenticated-orcid":false,"given":"Alexandra","family":"Lucaciu","sequence":"additional","affiliation":[{"name":"Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"},{"name":"Department of Neurology, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1948-7148","authenticated-orcid":false,"given":"Sumedha","family":"Inukollu","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Pondicherry University, Puducherry 605014, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8540-8093","authenticated-orcid":false,"given":"Rushendhiran","family":"Kesavan","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelie","family":"Janssen","sequence":"additional","affiliation":[{"name":"Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"Pfeilschifter","sequence":"additional","affiliation":[{"name":"Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9243-0558","authenticated-orcid":false,"given":"Julien","family":"Subburayalu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University Hospital Carl Gustav Carus TU Dresden, Fetscherstra\u00dfe 74, 01307 Dresden, Germany"},{"name":"Center for Regenerative Therapies Dresden (CRTD), TU Dresden, Fetscherstra\u00dfe 105, 01307 Dresden, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramesh K.","family":"Krishnan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology\/Oncology, University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"},{"name":"Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7890-9471","authenticated-orcid":false,"given":"Rajkumar","family":"Vutukuri","sequence":"additional","affiliation":[{"name":"Institute of General Pharmacology and Toxicology, Pharmazentrum Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/S0140-6736(24)00917-6","article-title":"Renal cell carcinoma","volume":"404","author":"Young","year":"2024","journal-title":"Lancet"},{"key":"ref_2","first-page":"11313","article-title":"Role of NF-\u03baB pathway in kidney renal clear cell carcinoma and its potential therapeutic implications","volume":"15","author":"Sun","year":"2023","journal-title":"Aging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.annonc.2024.05.537","article-title":"Renal cell carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"35","author":"Powles","year":"2024","journal-title":"Ann. 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