Rosiglitazone and trametinib exhibit potent anti-tumor activity in a mouse model of muscle invasive bladder cancer Journal Article
| Authors: | Plumber, S. A.; Tate, T.; Al-Ahmadie, H.; Chen, X.; Choi, W.; Basar, M.; Lu, C.; Viny, A.; Batourina, E.; Li, J.; Gretarsson, K.; Alija, B.; Molotkov, A.; Wiessner, G.; Lee, B. H. L.; McKiernan, J.; McConkey, D. J.; Dinney, C.; Czerniak, B.; Mendelsohn, C. L. |
| Article Title: | Rosiglitazone and trametinib exhibit potent anti-tumor activity in a mouse model of muscle invasive bladder cancer |
| Abstract: | Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients. © The Author(s) 2024. |
| Keywords: | immunohistochemistry; signal transduction; adult; cancer survival; controlled study; protein phosphorylation; unclassified drug; human cell; promoter region; genetics; monotherapy; nonhuman; antineoplastic agents; drug targeting; flow cytometry; antineoplastic agent; cell proliferation; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; cancer prevention; apoptosis; hepatocyte nuclear factor 3alpha; tumor volume; serine; transcription initiation; epidermal growth factor receptor 2; animal experiment; animal model; in vivo study; cell differentiation; caspase 3; antineoplastic activity; in vitro study; drug effect; pathology; cell line, tumor; pyrimidinone derivative; pyridones; pyrimidinones; fibroblast growth factor receptor 3; tumor marker; cancer model; bladder tumor; urinary bladder neoplasms; disease model; oncogene; urothelium; cancer regression; tumor cell line; drug response; fluorescence microscopy; cytokeratin 20; down regulation; neoplasm invasiveness; upregulation; cyclin dependent kinase inhibitor 1a; cytokeratin 19; cytokeratin; cytokeratin 14; tumor; drug therapy; disease models, animal; hermes antigen; cell nucleus receptor; peroxisome proliferator activated receptor gamma; ppar gamma; rosiglitazone; retinoic acid; ligand binding; growth differentiation factor 3; transcription factor e2f2; bladder carcinogenesis; retinoid; pathway analysis; cyclin dependent kinase 4; cyclin dependent kinase 1; muscle; mouse model; retinoids; antiproliferative activity; drug; antimicrobial activity; cyclin dependent kinase inhibitor 2b; muscle invasive bladder cancer; tumor invasion; thiazolidinediones; 2,4 thiazolidinedione derivative; retinal dehydrogenase; trametinib; combination drug therapy; kdm6a protein; cancer; humans; human; male; female; article; retinol binding protein 4; cytokeratin 16; carnitine palmitoyltransferase i; wild type mouse; swiss webster mouse; mrna expression level; protein expression level; invasive species; cytokeratin 6a; dipyrone; nf kb signaling; proapoptotic activity; nuclear receptor nr1d1; fatty acid binding protein 4; aldh1a1 protein; aldh1a2 protein; carnitine palmitoyltransferase 2; carnitine palmitoyltransferase ia; grhl3 protein; n butyl n (4 hydroxybutyl)nitrosamine; nuclear receptor nr1d2; nuclear receptor nr3cs; perilipin 4; rdh10 protein; upk1b protein; upk2 protein; upks protein; aplp2 gene; car3 gene; cyp26b1 gene; dhrs3 gene; dhrs4 gene; peg10 gene; ppar signaling; rarb gene; selenbp1 gene; stra6 gene |
| Journal Title: | Nature Communications |
| Volume: | 15 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-08-02 |
| Start Page: | 6538 |
| Language: | English |
| DOI: | 10.1038/s41467-024-50678-2 |
| PUBMED: | 39095358 |
| PROVIDER: | scopus |
| PMCID: | PMC11297265 |
| DOI/URL: | |
| Notes: | Source: Scopus |
