{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T21:09:12Z","timestamp":1785186552734,"version":"3.55.0"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,4,13]],"date-time":"2024-04-13T00:00:00Z","timestamp":1712966400000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Renal cell carcinoma (RCC) is the most common kidney cancer with high mortality rate. Pazopanib has been approved for the treatment of RCC. However, the underlying mechanism is not clear. Here, we report a novel finding by showing that treatment with Pazopanib could promote cellular senescence of the human RCC cell line ACHN. Cells were stimulated with 5, 10, and 20\u2009\u03bcM Pazopanib, respectively. Cellular senescence was measured using senescence\u2010associated \u03b2\u2010galactosidase (SA\u2010\u03b2\u2010Gal) staining. Western blot analysis and real\u2010time polymerase chain reaction\u00a0were used to measure the mRNA and protein expression of nuclear factor E2\u2010related factor 2 (Nrf2), \u03b3H2AX, human telomerase reverse transcriptase (hTERT), telomeric repeat binding factor 2 (TERF2), p53 and plasminogen activator inhibitor (PAI). First, we found that exposure to Pazopanib reduced the cell viability of ACHN cells. Additionally, Pazopanib induced oxidative stress \u00a0by increasing the production of reactive oxygen species,\u00a0reducing the levels of glutathione peroxidase,\u00a0and promoting nuclear translocation of Nrf2. Interestingly, Pazopanib exposure resulted in DNA damage by increasing the expression of \u03b3H2AX. Importantly, Pazopanib increased cellular senescence and reduced telomerase activity. Pazopanib also reduced the gene expression of hTERT but increased the gene expression of TERF2. Correspondingly, we found that Pazopanib increased the expression of p53 and PAI at both the mRNA and protein levels. To elucidate the underlying mechanism, the expression of Nrf2 was knocked down by transduction with Ad\u2010 Nrf2 shRNA. Results indicate that silencing of Nrf2 in ACHN cells abolished the effects of Pazopanib in stimulating cellular senescence and reducing telomerase activity. Consistently, knockdown of Nrf2 restored the expression of p53 and PAI in ACHN cells. Based on these results, we explored a novel mechanism whereby which Pazopanib displays a cytotoxicity effect in RCC cells through promoting cellular senescence mediated by Nrf2.<\/jats:p>","DOI":"10.1002\/jbt.23689","type":"journal-article","created":{"date-parts":[[2024,4,13]],"date-time":"2024-04-13T12:19:19Z","timestamp":1713010759000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pazopanib stimulates senescence of renal carcinoma cells through targeting nuclear factor E2\u2010related factor 2 (Nrf2)"],"prefix":"10.1002","volume":"38","author":[{"given":"Xingyuan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Urology Harbin Medical University Cancer Hospital Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology Harbin Medical University Cancer Hospital Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dechao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology Harbin Medical University Cancer Hospital Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lichen","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Urology Harbin Medical University Cancer Hospital Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongsheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Urology Harbin Medical University Cancer Hospital Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Orthognathic Surgery Heilongjiang Provincial Hospital Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology Harbin Medical University Cancer Hospital Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihao","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Urology Harbin Medical University Cancer Hospital Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9860-8485","authenticated-orcid":false,"given":"Changfu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology Harbin Medical University Cancer Hospital Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4,13]]},"reference":[{"issue":"3","key":"e_1_2_9_2_1","volume":"39","author":"Bahadoram S.","year":"2022","journal-title":"Giornale italiano di nefrologia: organo ufficiale della Societa italiana di nefrologia"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.14700"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-020-00359-2"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/JU.0000000000001063"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pathol.2020.10.002"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-018-0249-2"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2018.08.002"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00020.2018"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-0993"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1159\/000500683"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2021.107985"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000035222"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2022.04.068"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656560903436493"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0856"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1358\/dot.2009.45.9.1424750"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2021.108982"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom9080341"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgg.2013.05.007"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2011.07.014"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222313173"},{"key":"e_1_2_9_23_1","first-page":"168","volume":"29","author":"Regulski M. J.","year":"2017","journal-title":"Wounds"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-020-02842-y"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx684"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/gen039"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0110969"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2020.8043"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1038171"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2020.02.008"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-11-203"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309451"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2023.0208"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20174292"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7342"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21134777"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2022.04.003"}],"container-title":["Journal of Biochemical and Molecular Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbt.23689","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T04:31:06Z","timestamp":1718771466000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jbt.23689"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1002\/jbt.23689"],"URL":"https:\/\/doi.org\/10.1002\/jbt.23689","archive":["Portico"],"relation":{},"ISSN":["1095-6670","1099-0461"],"issn-type":[{"value":"1095-6670","type":"print"},{"value":"1099-0461","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4]]},"assertion":[{"value":"2023-11-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e23689"}}