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 (PGC1α), 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.

中文翻译：

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伊马替尼耐药胃肠道间质瘤中代谢脆弱性的异质性。

代谢重编程是癌细胞针对靶向治疗的标志。伊马替尼敏感性胃肠道间质瘤（GIST）已显示伊马替尼继发的线粒体呼吸功能增强，糖酵解活性降低。但是，能量代谢在伊马替尼耐药的GIST中的作用仍然很差。在这里，我们研究了伊马替尼治疗对糖酵解和氧化磷酸化（OXPHOS）的影响，以及在伊马替尼耐药和敏感的GIST细胞系中抑制这些能量代谢对细胞活力的影响。我们观察到伊马替尼治疗增加了对伊马替尼敏感但对伊马替尼耐药的GIST细胞中的OXPHOS。伊马替尼还降低了对伊马替尼敏感的GIST细胞中线粒体生物发生激活因子（过氧化物酶体增殖物激活受体共激活因子1α（PGC1α），核呼吸因子2（NRF2）和线粒体转录因子A（TFAM））的表达和线粒体质量。在伊马替尼敏感的GISTs中也观察到比未治疗患者的肿瘤中更低的TFAM水平。使用海马系统，我们观察到GIST细胞系之间的生物能学多样性。与亲本GIST 882相比，获得性抗药性细胞系之一（GIST 882R）表现出高代谢活性表型，具有更高的糖酵解和OXPHOS水平，而另一种抗药性细胞系（GIST T1R）具有相似的基础糖酵解活性，但线粒体呼吸作用较低比父母的GIST T1 进一步的功能分析表明，GIST 882R比GIST 882更容易受到糖酵解抑制作用，而GIST T1R比GIST T1对OXPHOS抑制作用更强。这些发现突显了GIST细胞中多种能量代谢适应性，使它们在伊马替尼治疗后得以存活，并揭示了针对GIST治疗靶向代谢的潜力。