Glucose is a potential source of glutamate for glutamine-deprived pancreatic cancer cells with KRAS mutation

Abstract

Pancreatic cancer is a highly lethal malignancy with a five-year survival of only 13% overall and 8% for pancreatic adenocarcinoma. KRAS mutations, present in over 90% of cases, drive oncogenesis and metabolic reprogramming, including a glycolytic switch. Glutamine and glutamate play interconnected roles in pancreatic cancer metabolism, with glutamine fueling CA19-9 biosynthesis via the hexosamine pathway. Son et al. (2013) identified a non-canonical glutamine metabolism pathway regulated by KRAS, where glutamine-derived aspartate is processed by GOT1 in the cytoplasm, bypassing GLUD1. However, pancreatic tumors are often nutrient-deficient, and under glutamine deprivation, cells may rewire glucose metabolism to generate glutamate. This study analyzed 684 pancreatic adenocarcinoma patients from a prospective database (2021-2025) and found that only 19.6% had normal fasting glucose, with high fasting blood glucose (≥126 mg/dL) being an adverse prognostic factor (HR=1.41, 95% CI 1.07-1.86, P=0.015). Using isotope tracing with D-glucose-13C6 in KRAS-mutated pancreatic cancer cells deprived of glutamine, we observed that glucose-derived carbons were incorporated into glutamate and related metabolites, including glycosylation precursors (UDP-GalNAc), collagen/stroma components (proline, 5-oxoproline), cell division metabolites (adenosine, AMP, ADP, etc.), and ROS-related molecules (GSH, GSSG, γ-glutamylcysteine) at 24h, with additional labeling in UDP-GlcNAc, glycine, and citrate at 48h. These findings suggest that glucose can serve as a potential source of glutamate under glutamine deprivation, providing a metabolic adaptation mechanism for KRAS-mutated pancreatic cancer cells. This rewiring may contribute to tumor progression and represents a potential therapeutic target.

1. Introduction

Pancreatic cancer is a highly lethal malignancy, with a five-year survival of only 13% for pancreatic cancer overall and just 8% for the most common form, pancreatic adenocarcinoma [1]. Its aggressive nature is driven by key molecular events. Specifically, KRAS mutations, which occur in over 90% of cases, act as pivotal oncogenic driver [2]. Concurrently, profound metabolic reprogramming is a hallmark of pancreatic cancer. Research indicates that a glycolytic switch is activated very early, even in precancerous lesions. This switch is driven by factors such as the transcription factor SP1, which promotes tumorigenesis by activating glycolytic enzymes. This rewired glucose metabolism not only fuels tumor growth but also helps cancer cells evade novel cell death mechanisms such as copper-dependent cuproptosis [2–4].

Glutamate and glutamine play interconnected and important roles in pancreatic cancer metabolism, with their dysregulation driving tumor progression. Glutamine fuels carbohydrate antigen 19-9 (CA19-9) biosynthesis via the hexosamine pathway, and its blockade suppresses tumor growth and metastasis, suggesting a potential therapeutic strategy [5]. Building on the seminal 2013 study by Son et al. [6], which investigated the unique metabolic dependencies of pancreatic cancer, this research focused on glutamine’s role. The study identified a critical, non-canonical glutamine metabolism pathway essential for pancreatic cancer tumor growth, regulated by the oncogenic KRAS mutation—a hallmark of this cancer. A major finding was that pancreatic cancer cells bypass the typical enzyme glutamate dehydrogenase (GLUD1) to channel glutamine into the tricarboxylic acid (TCA) cycle. Instead, they rely on a pathway where glutamine-derived aspartate is processed in the cytoplasm by aspartate transaminase (GOT1). Extracellular glutamine is the primary source for these cells. However, pancreatic tumors are often nutrient deficient. Under glutamine deprivation, the cells may rewire glucose metabolism to generate glutamate, utilizing pathways involving α-ketoglutarate and non-canonical TCA cycle routes [7].