HIF-1α regulates cellular metabolism, and Imatinib resistance by targeting phosphogluconate dehydrogenase in gastrointestinal stromal tumors

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.

Glucose transporter‑1 inhibition overcomes imatinib resistance in gastrointestinal stromal tumor cells

“…Imatinib resistance in GIST cells poses an additional obstacle due to limited availability of antitumor agents for unresectable GIST treatment (42)(43)(44)(45). Recent studies have reported that imatinib-resistant GIST cells exhibit high glycolysis rates (24,25), which may contribute to imatinib resistance. However, it was previously reported that imatinib-resistant GIST cells exhibited higher oxidative phosphorylation and higher glycolytic rates compared with those in imatinib-sensitive GIST cells (24).…”

“…However, it was previously reported that imatinib-resistant GIST cells exhibited higher oxidative phosphorylation and higher glycolytic rates compared with those in imatinib-sensitive GIST cells ( 24 ). However, the exact mechanism underlying the acquisition of imatinib resistance remains unclear, where a diverse range of metabolic modifications may be involved ( 24 , 25 , 46 ). In addition, it has been reported that the PI3K/AKT/mTOR pathway can be partially activated after secondary imatinib resistance in GIST ( 27 ).…”

“…Furthermore, high GLUT-1 expression has been linked to chemotherapeutic resistance in colon cancer and in head and neck cancer cell lines (22,23). Although a numerous studies have reported an association between imatinib resistance and increased rates of glycolysis (24)(25)(26)(27)(28), the mechanism of action and role of GLUT-1 underlying this entire process in GIST remains unclear.…”

Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors

“…Inhibition of OXPHOS increases the sensitivity of GISTs to IM. OXPHOS protein expression is increased in IM-sensitive GIST cells after IM treatment but not in IM-resistant GIST cells ( 47 ). Notably, there is a heterogeneity of metabolic phenotypes in IM-resistant GIST ( 40 ).…”

Impact of cancer metabolism on therapy resistance – Clinical implications

“…Pyruvate dehydrogenase kinase (PDK) is also transcriptionally activated by HIF-1α and is responsible for the inhibition of PDH, disconnecting the tricarboxylic acid (TCA) cycle from glycolysis and leading to a decrease in ATP and citrate by the mitochondria (Kim et al, 2006;Lu et al, 2008). A recent study by Xu et al showed a high PPP activity in imatinib-resistant gastrointestinal stromal tumors cell lines through a positive correlation between HIF-1α and PPP enzyme phosphogluconate dehydrogenase (PGD) (Xu et al, 2020). In this respect, HIF-1α has been studied in preclinical and clinical models as a therapeutic target in cancer resistance phenotypes once it might redirect aerobic glycolysis toward mitochondrial OXPHOS (Semenza, 2003;Shukla et al, 2017;Wei et al, 2020).…”