{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:02:19Z","timestamp":1791234139566,"version":"4.1.0"},"reference-count":80,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institute of Environmental Health Sciences of the National Institutes of Health","doi-asserted-by":"publisher","award":["R01ES030695"],"award-info":[{"award-number":["R01ES030695"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute of Environmental Health Sciences of the National Institutes of Health","doi-asserted-by":"publisher","award":["T32ES007255"],"award-info":[{"award-number":["T32ES007255"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Medicine pilot funds (MSU)","award":["R01ES030695"],"award-info":[{"award-number":["R01ES030695"]}]},{"name":"Department of Medicine pilot funds (MSU)","award":["T32ES007255"],"award-info":[{"award-number":["T32ES007255"]}]},{"name":"Cure Multiple Myeloma Corporation","award":["R01ES030695"],"award-info":[{"award-number":["R01ES030695"]}]},{"name":"Cure Multiple Myeloma Corporation","award":["T32ES007255"],"award-info":[{"award-number":["T32ES007255"]}]},{"DOI":"10.13039\/100000002","name":"National Institute of Environmental Health and Science Training Grant in Environmental Toxicology","doi-asserted-by":"publisher","award":["R01ES030695"],"award-info":[{"award-number":["R01ES030695"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute of Environmental Health and Science Training Grant in Environmental Toxicology","doi-asserted-by":"publisher","award":["T32ES007255"],"award-info":[{"award-number":["T32ES007255"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Obesity is not only a risk factor for multiple myeloma (MM) incidence, but it is also associated with an increased risk of progression from myeloma precursors\u2014monoclonal gammopathy of undetermined significance\u2014and smoldering myeloma. Adipocytes in the bone marrow (BMAs) microenvironment have been shown to facilitate MM cell growth via secreted factors, but the nature of these secreted factors and their mechanism of action have not been fully elucidated. The elevated expression of aryl hydrocarbon receptor (AhR) is associated with a variety of different cancers, including MM; however, the role of AhR activity in obesity-associated MM cell growth and survival has not been explored. Indeed, this is of particular interest as it has been recently shown that bone marrow adipocytes are a source of endogenous AhR ligands. Using multiple in vitro models of tumor\u2013adipocyte crosstalk to mimic the bone microenvironment, we identified a novel, non-toxicological role of the adipocyte-secreted factors in the suppression of AhR activity in MM cells. A panel of six MM cell lines were cultured in the presence of bone marrow adipocytes in (1) a direct co-culture, (2) a transwell co-culture, or (3) an adipocyte-conditioned media to interrogate the effects of the secreted factors on MM cell AhR activity. Nuclear localization and the transcriptional activity of the AhR, as measured by CYP1A1 and CYP1B1 gene induction, were suppressed by exposure to BMA-derived factors. Additionally, decreased AhR target gene expression was associated with worse clinical outcomes. The knockdown of AhR resulted in reduced CYP1B1 expression and increased cellular growth. This tumor-suppressing role of CYP1A1 and CYP1B1 was supported by patient data which demonstrated an association between reduced target gene expression and worse overall survival. These data demonstrated a novel mechanism by which bone marrow adipocytes promote MM progression.<\/jats:p>","DOI":"10.3390\/cancers15215255","type":"journal-article","created":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T07:24:04Z","timestamp":1698823444000},"page":"5255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Non-Toxicological Role of Aryl Hydrocarbon Receptor in Obesity-Associated Multiple Myeloma Cell Growth and Survival"],"prefix":"10.3390","volume":"15","author":[{"given":"Jonathan D.","family":"Diedrich","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig E.","family":"Cole","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology\/Oncology, Michigan State University, East Lansing, MI 48910, USA"},{"name":"Karmanos Cancer Institute, McLaren Greater Lansing, Lansing, MI 48910, USA"},{"name":"Department of Medicine, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Pianko","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology\/Oncology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5882-4569","authenticated-orcid":false,"given":"Justin A.","family":"Colacino","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie J.","family":"Bernard","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA"},{"name":"Department of Medicine, Michigan State University, East Lansing, MI 48824, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1023\/A:1022268103136","article-title":"Myeloma and race: A review of the literature","volume":"22","author":"Benjamin","year":"2003","journal-title":"Cancer Metastasis Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1182\/blood-2010-01-262394","article-title":"Obesity is associated with an increased risk of monoclonal gammopathy of undetermined significance among black and white women","volume":"116","author":"Landgren","year":"2010","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1182\/blood-2005-08-3449","article-title":"Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States","volume":"107","author":"Landgren","year":"2006","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Padala, S.A., Barsouk, A., Barsouk, A., Rawla, P., Vakiti, A., Kolhe, R., Kota, V., and Ajebo, G.H. 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