The pentose phosphate pathway (PPP) plays a critical role in maintaining cellular redox homeostasis in tumor cells and macromolecule biosynthesis. Upregulation of the PPP has been shown in several types of tumor. However, how the PPP is regulated to confer selective growth advantages on drug resistant tumor cells is not well understood. Here we show a metabolic shift from tricarboxylic acid cycle (TCA) to PPP after a long period induction of Imatinib (IM). One of the rate-limiting enzymes of the PPP-phosphogluconate dehydrogenase (PGD), is dramatically upregulated in gastrointestinal stromal tumors (GISTs) and GIST cell lines resistant to Imatinib (IM) compared with sensitive controls. Functional studies revealed that the overexpression of PGD in resistant GIST cell lines promoted cell proliferation and suppressed cell apoptosis. Mechanistic analyses suggested that the protein level of hypoxia inducible factor-1α (HIF-1α) increased during long time stimulation of reactive oxygen species (ROS) produced by IM. Importantly, we further demonstrated that HIF-1α also had positive correlation with PGD, resulting in the change of metabolic pathway, and ultimately causing drug resistance in GIST. Our findings show that long term use of IM alters the metabolic phenotype of GIST through ROS and HIF-1α, and this may contribute to IM resistance. Our work offers preclinical proof of metabolic target as an effective strategy for the treatment of drug resistance in GIST.

译文

磷酸戊糖途径(PPP)在维持肿瘤细胞中细胞氧化还原稳态和大分子生物合成中起关键作用。 PPP的上调已在几种类型的肿瘤中显示出来。然而,如何调节PPP以赋予抗药性肿瘤细胞选择性生长优势尚不清楚。在这里,我们显示了伊马替尼(IM)的长期诱导后从三羧酸循环(TCA)到PPP的代谢转变。与敏感对照相比,PPP-磷酸葡糖酸脱氢酶(PGD)的一种限速酶在胃肠道间质瘤(GIST)和对伊马替尼(IM)具有抗性的GIST细胞系中显着上调。功能研究表明,抗性GIST细胞系中PGD的过度表达促进细胞增殖并抑制细胞凋亡。机理分析表明,在长时间刺激IM产生的活性氧(ROS)后,缺氧诱导因子1α(HIF-1α)的蛋白水平升高。重要的是,我们进一步证明了HIF-1α也与PGD呈正相关,从而导致了代谢途径的改变,并最终导致了GIST的耐药性。我们的发现表明,长期使用IM会通过ROS和HIF-1α改变GIST的代谢表型,这可能会导致IM抵抗。我们的工作提供了代谢靶点的临床前证据,作为治疗GIST耐药性的有效策略。

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