{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T22:17:53Z","timestamp":1776377873761,"version":"3.51.2"},"reference-count":74,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T00:00:00Z","timestamp":1633996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA123362"],"award-info":[{"award-number":["CA123362"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>A hallmark of malignant solid tumor is extracellular acidification coupled with metabolic switch to aerobic glycolysis. Using the human MCF10A progression model of breast cancer, we show that glycolytic switch and extracellular acidosis in aggressive cancer cells correlate with increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), known to induce intracellular signal transduction through the interaction with its cell surface receptor CD63, independent of its metalloproteinase inhibitory function. We found that, in aggressive breast carcinoma, the TIMP-1\u2013CD63 signaling axis induced a metabolic switch by upregulating the rate of aerobic glycolysis, lowering mitochondrial respiration, preventing intracellular acidification, and inducing extracellular acidosis. Carbonic anhydrase IX (CAIX), a regulator of cellular pH through the hydration of metabolically released pericellular CO2, was identified as a downstream mediator of the TIMP-1\u2013CD63 signaling axis responsible for extracellular acidosis. Consistently with our previous study, the TIMP-1\u2013CD63 signaling promoted survival of breast cancer cells. Interestingly, breast carcinoma cell survival was drastically reduced upon shRNA-mediated knockdown of CAIX expression, demonstrating the significance of CAIX-regulated pH in the TIMP-1\u2013CD63-mediated cancer cell survival. Taken together, the present study demonstrates the functional significance of TIMP-1\u2013CD63\u2013CAXI signaling axis in the regulation of tumor metabolism, extracellular acidosis, and survival of breast carcinoma. We propose that this axis may serve as a novel therapeutic target.<\/jats:p>","DOI":"10.3390\/cells10102721","type":"journal-article","created":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T08:09:32Z","timestamp":1634026172000},"page":"2721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Regulation of Tumor Metabolism and Extracellular Acidosis by the TIMP-10\u2013CD63 Axis in Breast Carcinoma"],"prefix":"10.3390","volume":"10","author":[{"given":"Abdo J.","family":"Najy","sequence":"first","affiliation":[{"name":"Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0299-4451","authenticated-orcid":false,"given":"Young-Suk","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1120-073X","authenticated-orcid":false,"given":"Seongho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Fridman","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA"},{"name":"Department of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7960-0580","authenticated-orcid":false,"given":"Hyeong-Reh C.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA"},{"name":"Department of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1126\/science.1160809","article-title":"Understanding the warburg effect: The metabolic requirements of cell proliferation","volume":"324","author":"Cantley","year":"2009","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/s42255-020-0172-2","article-title":"We need to talk about the warburg effect","volume":"2","author":"Chandel","year":"2020","journal-title":"Nat. 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