Rakus, D. | bioRxiv Science

bioRxiv2025

Metabolic Collapse in Pancreatic Cancer via Combined Inhibition of Lactate Export and Thioredoxin Reductase

Pancreatic cancer is one of the most poorly prognosed types of cancer, with a low survival rate. Cancer cells exhibit altered and rapid metabolism, and in a process known as aerobic glycolysis, they metabolize glucose to lactate even in the presence of sufficient oxygen. Altered metabolism is a hallmark of cancer, making it a promising therapeutic target. There are many potential inhibitors of cancer cell metabolism, including auranofin and syrosingopine. Auranofin induces oxidative stress in cells by generating reactive oxygen species (ROS). Meanwhile, syrosingopine is an inhibitor of the two lactate transporters, MCT1 and MCT4, which contribute to intracellular acidification. Our studies demonstrated the high biological activity of the combination of auranofin and syrosingopine against pancreatic cancer in both in vitro and in vivo models. Our proposed mechanism of action for this drug combination is based on the simultaneous induction of oxidative stress and inhibition of lactate transporters, which consequently directs cancer cells to the apoptosis pathway.

cancer biology↗

bioRxiv2025

Glucose-dependent metabolism of hippocampal primary neurons in response to chemically induced long-term potentiation

Glucose is a predominant fuel for the brain supporting its high energy demand associated with neuronal signaling and synaptic activity. Long-term potentiation (LTP) is required for learning and memory formation by generating long lasting increase in synaptic strength and signal transmission between two neurons. While the electrophysiological bases of LTP are well established, much less is known about the metabolic demands of neurons involved in LTP. Common protocols used to examine synaptic activity rely on high glucose concentrations which are far from physiological glucose levels found in the brain. Here we used primary hippocampal neurons cultured under physiological (2.5 mM) and high (25 mM) glucose to investigate the metabolic effects of chemically induced LTP. Physiological glucose was associated with neuronal survival while high glucose promoted "PAS granule" accumulation. Changes in glucose altered extracellular lactate and pyruvate concentrations and affected key intracellular metabolic intermediates and neurotransmitter levels in neuronal cells without depleting the TCA cycle. LTP induction was comparable, but mitochondrial and neurotransmitter response to LTP was differentially affected physiological and high glucose conditions. Glycogen phosphorylase inhibition had minimal effects in physiological glucose but impaired synaptic responses and altered metabolite dynamics in high glucose. Our findings demonstrate that neuronal mitochondrial metabolism is closely linked to synaptic plasticity and highlight the importance of studying neurophysiological activity physiologically relevant glucose conditions.

neuroscience↗