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.

• Authors: Kangjing Xu, Zhongyuan He, Ming Chen, Nuofan Wang, Diancai Zhang, Li Yang, Zekuan Xu, Hao Xu
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 7 Pg. 586 (07 27 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 32719331 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Reactive Oxygen Species
• Imatinib Mesylate
• Phosphogluconate Dehydrogenase

Topics

• Animals
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gastrointestinal Stromal Tumors (enzymology, metabolism, pathology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Imatinib Mesylate (pharmacology)
• Male
• Mice, Nude
• Middle Aged
• Models, Biological
• Phosphogluconate Dehydrogenase (antagonists & inhibitors)
• Reactive Oxygen Species (metabolism)
• Up-Regulation (drug effects)