{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T15:40:59Z","timestamp":1768750859251,"version":"3.49.0"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T00:00:00Z","timestamp":1608163200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81802691"],"award-info":[{"award-number":["81802691"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Physiology"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:sec><jats:title>New Findings<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item>\n<jats:p><jats:bold>What is the central question of this study?<\/jats:bold><\/jats:p>\n<jats:p>Carfilzomib, a second\u2010generation proteasome inhibitor approved for the treatment of multiple myeloma, shows efficacy against osteosarcoma. However, drug resistance remains a major challenge. What is the role of carfilzomib\u2010induced changes in mitogen\u2010activated protein kinase (MAPK) pathways in the sensitivity of osteosarcoma cells to the proapoptotic effects of the drug?<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p><jats:bold>What is the main finding and its importance?<\/jats:bold><\/jats:p>\n<jats:p>The dose\u2010dependent antiapoptotic effects in osteosarcoma are associated with activation of MAPK signalling. Combinational targeting of MAPK signalling pathways can synergistically enhance carfilzomib\u2010induced cell apoptosis, suggesting that MAPK inhibitors in combination with proteasome inhibitors can serve as a novel therapeutic tool for osteosarcoma.<\/jats:p>\n<\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Osteosarcoma is the most common primary bone malignancy. Despite efforts to improve outcomes, the overall survival rates for osteosarcoma have remained unchanged over the past three decades. In this study, we assessed the proapoptotic effects of the second\u2010generation proteasome inhibitor carfilzomib on osteosarcoma and investigated the potential mechanisms underlying the synergistic proapoptotic action when combined with mitogen\u2010activated protein kinase (MAPK) inhibitors. We found that carfilzomib alone significantly inhibited cell proliferation and induced apoptosis in a dose\u2010dependent manner, characterized by the induction of cleaved caspase 3 and poly (ADP\u2010ribose) polymerase. More importantly, focusing on the changes of antiapoptotic B\u2010cell lymphoma 2 (Bcl\u20102) family members and signalling pathways, we found a striking induction of myeloid cell leukaemia 1 (Mcl\u20101) and the activation of MAPK pathways. Furthermore, we observed that combinational targeting of the MAPK pathways using the specific inhibitors U0126, SP600125 or SB203580 synergistically enhanced carfilzomib\u2010induced cell apoptosis. Notably, we found that the combinational inhibition of extracellular signal\u2010regulated kinase or c\u2010Jun N\u2010terminal kinase MAPK pathways significantly decreased the expression of the three antiapoptotic Bcl\u20102 family proteins, and in particular this reversed induction of Mcl\u20101 by carfilzomib. Collectively, our findings show that activation of the MAPK pathways contributes to the mechanisms of drug resistance to carfilzomib. In addition, the synergistic proapoptotic action of MAPK and proteasome inhibitors in osteosarcoma cells suggests that combinational therapy with both drug types may serve as a novel strategy for the clinical management of osteosarcoma.<\/jats:p><\/jats:sec>","DOI":"10.1113\/ep088762","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T14:49:12Z","timestamp":1608302952000},"page":"438-449","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Resistance of osteosarcoma cells to the proapoptotic effects of carfilzomib involves activation of mitogen activated protein kinase pathways"],"prefix":"10.1113","volume":"106","author":[{"given":"Li","family":"Lei","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Genetics Xi'an Jiaotong University Health Science Center  Xi'an Shaanxi 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