Abstract
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.
Highlights
Gastrointestinal stromal tumor (GIST) is the most common sarcoma[1], often harboring gain-of-function mutations in the KIT receptor tyrosine kinase[2]
In the course of culturing the resistant cell lines, we found that in GIST-T1R and GIST-882R cells, the color of the culture medium changed from pink to orange more rapidly and the pH of the medium decreased from 7.7 to 6.4 at day 3 (Supplementary Fig. 1A)
CCK-8 assays were performed to found that optical density (OD) values displayed no changes at day 3, excluding the possibility that the changes of pH caused by the difference of cell numbers (Supplementary Fig. 1B, C)
Summary
Gastrointestinal stromal tumor (GIST) is the most common sarcoma[1], often harboring gain-of-function mutations in the KIT receptor tyrosine kinase[2]. While IM has revolutionized the treatment of GIST through targeting KIT3, resistance and disease progression often develop within 2 years[4]. The metabolic flux in tumor cells is markedly reprogrammed to provide elevated amounts of building blocks for rapid cell growth and metastasis[9,10]. It is not well understood how tumor cells reset the metabolic phenotype to promote tumor cell survival and cell proliferation.
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