{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T11:25:09Z","timestamp":1773660309827,"version":"3.50.1"},"reference-count":41,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2020,7,30]],"date-time":"2020-07-30T00:00:00Z","timestamp":1596067200000},"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":["81702664"],"award-info":[{"award-number":["81702664"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["iubmb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["IUBMB Life"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Osteosarcoma (OS) is a malignant bone neoplasm, mostly occurring in pediatric patients. OS is characterized by a highly aggressive and metastatically active tumor. Chemotherapy followed by surgical excision is the treatment of choice but is often associated with both chemoresistance and relapse. Hence, it is important to develop further understanding of OS pathogenesis and identify potential therapeutic targets. Both the signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) have been implicated in OS pathogenesis. Crosstalk between mTOR and STAT3 signaling has been shown to regulate hypoxia\u2010induced angiogenesis in other diseases. In this study, we determined using OS cell lines if there is a crosstalk between these two pathways and how that impacts sensitivity to treatment with Rapamycin. OS cell lines exhibited differential sensitivity to mTOR inhibitor Rapamycin. Evaluation of phosphorylated STAT3 showed that in Rapamycin\u2010sensitive 143B cells, the inhibitor decreased phosphorylation of STAT3 at Y705, but not at S727 whereas, in Rapamycin\u2010resistant U2OS cells, the inhibitor decreased S727 phosphorylation but not Y705. However, knockdown of <jats:italic>STAT3<\/jats:italic> in U2OS cells made them sensitive to Rapamycin. Immunofluorescence (IF) analysis showed that mTOR is constitutively activated in the 143B cells but is suppressed in the U2OS cells, indicating that this might be their reason for being resistant to Rapamycin. Both cell lines were sensitive to treatment with the STAT3 inhibitor Napabucasin (NP). Treatment with NP inhibited STAT3 activation at Y705 and additionally inhibited mTOR activation, indicating crosstalk between STAT3 and mTOR signaling pathways. Rapamycin could effectively prevent lung metastasis in an orthotropic OS mice model using 143B cells. However, Rapamycin could not inhibit lung metastasis in mice injected with U2OS cells. The STAT3 inhibitor NP attenuated lung metastasis with the U2OS cells. Our results thus established yet undefined crosstalk of STAT3 and mTOR signaling pathways in OS and highlight the possibility of using mTOR inhibitors for treatment in patients with OS.<\/jats:p>","DOI":"10.1002\/iub.2349","type":"journal-article","created":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T04:28:33Z","timestamp":1596169713000},"page":"2146-2153","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Role of crosstalk between <scp>STAT3<\/scp> and <scp>mTOR<\/scp> signaling in driving sensitivity to chemotherapy in osteosarcoma cell lines"],"prefix":"10.1002","volume":"72","author":[{"given":"Yi\u2010tian","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedics West China Hospital, Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics West China Hospital, Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics West China Hospital, Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuan\u2010xi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Orthopedics West China Hospital, Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao\u2010jun","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Orthopedics West China Hospital, Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Orthopedics West China Hospital, Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Orthopedics West China Hospital, Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8704-8805","authenticated-orcid":false,"given":"Li","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Orthopedics West China Hospital, Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,7,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/14737140.2018.1413939"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.21088"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm5110096"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-3640"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6855"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3025"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.2217\/fon-2016-0261"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11912-007-0039-7"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-10-187"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11912-018-0658-1"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.90449"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1066015"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2014.00064"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.07.003"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00133"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-1125"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbo.2018.07.010"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2007-0171"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0b013e3181c2d2b4"},{"key":"e_1_2_8_21_1","first-page":"1813","article-title":"NCCN pediatric neuroblastoma practice guidelines. 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