{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:17:45Z","timestamp":1789777065297,"version":"4.0.1"},"reference-count":42,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T00:00:00Z","timestamp":1590451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007232","name":"Radiumhemmets Forskningsfonder","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100007232","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Metabolic reprogramming is a hallmark of cancer cells in response to targeted therapy. Decreased glycolytic activity with enhanced mitochondrial respiration secondary to imatinib has been shown in imatinib-sensitive gastrointestional stromal tumors (GIST). However, the role of energy metabolism in imatinib-resistant GIST remains poorly characterized. Here, we investigated the effect of imatinib treatment on glycolysis and oxidative phosphorylation (OXPHOS), as well as the effect of inhibition of these energy metabolisms on cell viability in imatinib-resistant and -sensitive GIST cell lines. We observed that imatinib treatment increased OXPHOS in imatinib-sensitive, but not imatinib-resistant, GIST cells. Imatinib also reduced the expression of mitochondrial biogenesis activators (peroxisome proliferator-activated receptor coactivator-1 alpha (PGC1\u03b1), nuclear respiratory factor 2 (NRF2), and mitochondrial transcription factor A (TFAM)) and mitochondrial mass in imatinib-sensitive GIST cells. Lower TFAM levels were also observed in imatinib-sensitive GISTs than in tumors from untreated patients. Using the Seahorse system, we observed bioenergetics diversity among the GIST cell lines. One of the acquired resistant cell lines (GIST 882R) displayed a highly metabolically active phenotype with higher glycolysis and OXPHOS levels compared with the parental GIST 882, while the other resistant cell line (GIST T1R) had a similar basal glycolytic activity but lower mitochondrial respiration than the parental GIST T1. Further functional assays demonstrated that GIST 882R was more vulnerable to glycolysis inhibition than GIST 882, while GIST T1R was more resistant to OXPHOS inhibition than GIST T1. These findings highlight the diverse energy metabolic adaptations in GIST cells that allow them to survive upon imatinib treatment and reveal the potential of targeting the metabolism for GIST therapy.<\/jats:p>","DOI":"10.3390\/cells9061333","type":"journal-article","created":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T00:44:02Z","timestamp":1590713042000},"page":"1333","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Heterogeneity of Metabolic Vulnerability in Imatinib-Resistant Gastrointestinal Stromal Tumor"],"prefix":"10.3390","volume":"9","author":[{"given":"Wen-Kuan","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, SE-17164 Solna, Sweden"},{"name":"Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwei","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, SE-17164 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, SE-17164 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, SE-17164 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, Karolinska Institutet, Solnav\u00e4gen 9, SE-17165 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanhuan L.","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Medicine-Solna, Microbial Pathogenesis Unit, Karolinska Institutet, BioClinicum, SE-17164 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1455-092X","authenticated-orcid":false,"given":"Chun-Nan","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Surgery, Chang Gung Memorial Hospital and GIST team at Linkou, Chang Gung University College of Medicine, Taoyuan 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Br\u00e4nstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharina","family":"Larsson","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, SE-17164 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4717-4473","authenticated-orcid":false,"given":"Shuijie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weng-Onn","family":"Lui","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, SE-17164 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1177\/106689690000800105","article-title":"Molecular Insights into the Histogenesis and Pathogenesis of Gastrointestinal Stromal Tumors","volume":"8","author":"Rubin","year":"2000","journal-title":"Int. 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