Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells

Abstract

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR–IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer.

Cyclin F-Dependent Degradation of RBPJ Inhibits IDH1R132H-Mediated Tumorigenesis

“…In pancreatic cancer cells, HuR, a RNA-binding protein binds to and stabilizes IDH1 transcript. Elevated IDH1 levels promote chemoresistance in these cells by augmenting antioxidant defense mechanism (36). A recent report suggests that exogenously expressed FOXO3A transactivates IDH1.…”

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

“…Cells were plated in 96-well plates at 10 3 cells per well and treated the next day with THZ1 at various concentrations. After 5 d of incubation, cell growth was measured using Quant-it PicoGreen dsDNA assay kit (Invitrogen; Zarei et al, 2017). To estimate cell death, cells were trypsinized and counted after Trypan blue staining (Invitrogen) with a Hausser brightline hemocytometer (Thermo Fisher Scientific).…”

The Landscape of the Anti-Kinase Activity of the IDH1 Inhibitors

“…Cancer cells are characterized by an accelerated metabolism and an increased demand for glucose and other nutrients. Therefore, the overexpression of the wild-type IDH1 is often associated with the uncontrolled growth and survival of numerous cancers, including non-small cell lung carcinoma [9], primary glioblastomas (GBMs) [10], pancreatic ductal adenocarcinoma [11] and several hematological malignancies such as lymphomas or leukemias [12,13]. On the other hand, mutations of the genes encoding the IDH1 enzyme have also been found in several cancers, mainly in about 80% of low-grade gliomas and secondary GBMs, about 40% of T cell lymphomas and in about of 10% of myeloid leukemias [13,14].…”