<b>Metabolic profiling of gemcitabine- and paclitaxel-treated immortalized human pancreatic cell lines with K-RAS</b>^{<b>G12D </b>}

Abstract

The mechanisms of action of gemcitabine (GEM) and paclitaxel (PTX) have been well investigated, and shown to be the inhibition of DNA polymerase and polymerization of tubulin, respectively. Meanwhile, genomic research has revealed that mutations in the K-RAS oncogene occur in over 90% of pancreatic cancer. Oncogenic alteration rewires alternative metabolic pathways to satisfy the demands of growth. The K-RAS oncogene also has been shown to upregulate glycolysis and glutaminolysis. However, it is still unclear whether K-RAS independently plays a central role in controlling tumor metabolism. Here, we conducted a metabolomic analysis of a simple oncogenic K-RAS cell line model constructed using human telomerase catalytic subunit-immortalized human pancreatic epithelial nestin-expressing cell lines with and without K-RAS G12D . We also investigated the effect of GEM and PTX on these cells. As a result, it was shown in the cell with K-RAS G12D that the level of lactate was increased and glutamic acid, glutamine, and aspartic acid levels were decreased. In the nucleotide metabolism, GEM-treated cells showed metabolic changes, whereas these phenomena were not observed in PTX-treated cells. In conclusion, it was suggested that K-RAS G12D independently modified tumor metabolism and the difference between GEM and PTX in the nucleotide metabolism was revealed.Pancreatic cancer is the fourth-leading cause of cancer-related death in Japan and the USA (25). Surgical resection is the only potentially curative treatment, but the majority of patients have unresectable disease at the time of diagnosis due to distant metastasis or vascular involvement. Gemcitabine tetrahydrofuran-2-yl]-1H-pyrimidin-2-one) monotherapy became a standard treatment for unresectable pancreatic cancer after it demonstrated superior clinical benefit over 5-fluorouracil (3). Median overall survival for patients who received GEM monotherapy for advanced pancreatic cancer in key trials has ranged from 5.7-6.2 months (3,22). Numerous phase III trials of other treatments have failed to meaningfully improve overall survival over GEM monotherapy (18,14,28). Although GEM plus erlo-

Mass Spectrometry-Based Method to Study Inhibitor-Induced Metabolic Redirection in the Central Metabolism of Cancer Cells

“…This is because metabolic profiling of paclitaxel treatment using immortalized human pancreatic cell lines showed no significant changes in central metabolism. 40 ) However, a comparison of estimated metabolic flux distributions in this study clearly indicated that paclitaxel treatment reduced metabolic flux into the EMP pathway that converts glucose into lactate for anaerobic glycolysis (blue arrows in Fig. 4b ).…”

LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer

“…Reprogrammed energy metabolism has become an emerging hallmark of cancer in recent years [ 3 ]. Previous studies indicated that most metabolites did not show significant changes in pancreatic cancer cells exposed to GEM; however, chemoresistance to GEM induces metabolic reprogramming [ 4 , 5 ]. Therefore, metabolic reprogramming must be involved in the regulation of chemoresistance.…”

Low-Dose Paclitaxel Inhibits Tumor Cell Growth by Regulating Glutaminolysis in Colorectal Carcinoma Cells

“…Moreover, inhibition of glutaminolysis increased lactate production in several types of tumors (Draoui and Feron, 2011; Todaka et al, 2017). Consistent with these results, we found that low-dose PTX down-regulated expression of glutaminolysis-related genes ( GLS, SLC7A11 and SLC1A5 ) and increased lactate production in HCT116 cells ( Figures 3C, 5 ).…”