{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:17:33Z","timestamp":1787015853874,"version":"build-2736575974"},"reference-count":49,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T00:00:00Z","timestamp":1639440000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pigment Cell Melanoma Res"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Melanoma is highly heterogeneous with diverse genomic alterations and partial therapeutic responses. The emergence of drug\u2010resistant tumor cell clones accompanied by a high AXL expression level is one of the major challenges for anti\u2010tumor clinical care. Recent studies have demonstrated that high AXL expression in melanoma cells mediated drug resistance, epithelial\u2010mesenchymal transition (EMT), and elevated survival of cancer stem cells (CSCs). Given that we have identified several non\u2010steroidal anti\u2010inflammatory drugs (NSAIDs) including aspirin potently induce the degradation of AXL, we questioned whether NSAIDs could counteract the AXL\u2010mediated neoplastic phenotypes. In this study, we found that NSAIDs downregulate PKA activity via the PGE\n                    <jats:sub>2<\/jats:sub>\n                    \/EP2\/cAMP\/PKA signaling pathway and interrupt the PKA\u2010dependent interaction between CDC37 and HSP90, resulting in an incorrect AXL protein folding and finally AXL degradation through the ubiquitination\u2010proteasome system (UPS) pathway. Furthermore, NSAIDs not only sensitized the MEK inhibitor treatment but also reduced EMT and relapse mediated by AXL in tumor tissue. Our findings suggest that the combination of inhibitors and NSAIDs, especially aspirin, could be a simple but efficient modality to treat melanoma in which AXL is a key factor for drug resistance, metastasis, and relapse.\n                  <\/jats:p>","DOI":"10.1111\/pcmr.13021","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T11:03:15Z","timestamp":1636369395000},"page":"238-251","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Non\u2010Steroidal Anti\u2010Inflammatory Drugs (NSAIDs) sensitize melanoma cells to MEK inhibition and inhibit metastasis and relapse by inducing degradation of AXL"],"prefix":"10.1111","volume":"35","author":[{"given":"Yingshi","family":"Chen","sequence":"first","affiliation":[{"name":"Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Disease Control of Ministry of Education Institute of Human Virology Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology Zhongshan School of Medicine Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China Cancer Center Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Disease Control of Ministry of Education Institute of Human Virology Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology Zhongshan School of Medicine Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingtong","family":"Lin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Disease Control of Ministry of Education Institute of Human Virology Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology Zhongshan School of Medicine Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou China"},{"name":"Key Laboratory of Tropical Disease Control of Ministry of Education Institute of Human Virology Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology Zhongshan School of Medicine Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1546-9365","authenticated-orcid":false,"given":"Fei","family":"Yu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.0017"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.57"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2422"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476\u20105381.2011.01494.x"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4472"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/jclinpath-2016-203629"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(11)61049\u20100"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201012\u20101558"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201017\u20100242"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.03.010"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2016.428"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909333107"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201015\u20100439"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2006.04.004"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-2118"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201009\u20102997"},{"issue":"11","key":"e_1_2_8_18_1","first-page":"2113","article-title":"A novel putative tyrosine kinase receptor with oncogenic potential","volume":"6","author":"Janssen J. 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