Endoplasmic Reticulum Stress and Its Role in Metabolic Reprogramming of Cancer

Abstract

Background/Objectives: Endoplasmic reticulum (ER) stress occurs when ER homeostasis is disrupted, leading to the accumulation of misfolded or unfolded proteins. This condition activates the unfolded protein response (UPR), which aims to restore balance or trigger cell death if homeostasis cannot be achieved. In cancer, ER stress plays a key role due to the heightened metabolic demands of tumor cells. This review explores how metabolomics can provide insights into ER stress-related metabolic alterations and their implications for cancer therapy. Methods: A comprehensive literature review was conducted to analyze recent findings on ER stress, metabolomics, and cancer metabolism. Studies examining metabolic profiling of cancer cells under ER stress conditions were selected, with a focus on identifying potential biomarkers and therapeutic targets. Results: Metabolomic studies highlight significant shifts in lipid metabolism, protein synthesis, and oxidative stress management in response to ER stress. These metabolic alterations are crucial for tumor adaptation and survival. Additionally, targeting ER stress-related metabolic pathways has shown potential in preclinical models, suggesting new therapeutic strategies. Conclusions: Understanding the metabolic impact of ER stress in cancer provides valuable opportunities for drug development. Metabolomics-based approaches may help identify novel biomarkers and therapeutic targets, enhancing the effectiveness of antitumor therapies.

Keywords: biochemical pathways; cancer; drug discovery; endoplasmic reticulum stress; metabolomics; tumor microenvironment; unfolded protein response.

Figure 1

Schematic representation of the main metabolic pathways involved in cancer. The Warburg effect describes the preference for aerobic glycolysis over oxidative phosphorylation, even in the presence of oxygen. In tumors, the upregulation of glucose transporters, such as GLUT1, promotes glucose uptake, which fuels glycolysis: it converts glucose into pyruvate, which is subsequently transformed into acetyl-CoA, feeding the TCA cycle. This process generates ATP and key intermediates such as citrate and α-ketoglutarate (α-KG), essential for fatty acid synthesis. Glucose is also directed into the pentose phosphate pathway (PPP), generating ribose-5-phosphate and NADPH, necessary for redox balance. The generated pyruvate is reduced to lactate by LDH, and the excess lactate produced by cells is exported into the extracellular space via monocarboxylate transporters MCT4 (monocarboxylate transporter 4). Glutamine participates in glutaminolysis, a process that converts glutamine to glutamate (Glu), via glutaminase (GLS), and then to α-ketoglutarate, fueling the TCA cycle. Glutamate is a precursor in the synthesis of glutathione (GSH), which is a potent antioxidant. In cancer, MYC and RAS promote glucose uptake and regulate glutamine metabolism. In the tumor microenvironment, alanine metabolism contributes to protein biosynthesis and acts as an anaplerotic substrate to replenish TCA cycle intermediates. Arginine is converted to nitric oxide (NO) via nitric oxide synthesis (NOS). ADC (arginine decarboxylase) catalyzes the decarboxylation of arginine, converting it to agmatine. Arginine enters the urea cycle and is converted to ornithine. Ornithine, via ornithine decarboxylase (ODC), forms polyamines, which, together with NO, are involved in tumor growth. Carnitine may help cancer cells adapt to low-oxygen conditions by providing an alternative energy source that is less reliant on glycolysis. Created with BioRender.com.

Figure 2

Schematic representation of the main metabolic pathways involved in cancer. In tumors, elevated carnitine is associated with increased fatty acid oxidation and increased mitochondrial function. In cancer cells, glucose is the major carbon source for fatty acid synthesis: glucose is converted to acetyl-CoA and then to citrate in the mitochondria. The enzyme ACLY cleaves citrate to produce acetyl-CoA, which is used for the biosynthesis of fatty acids and cholesterol. Alterations in phospholipid (lysoPL) compositions, triggered by iPLA₂ (calcium-independent phospholipase A₂), are linked to tumor progression. Cholesterol-rich lipid rafts in cancer cell membranes act as platforms for receptor clustering and signal transduction, enhancing pathways such as PI3K/protein kinase B (Akt). Cholesterol and lipid accumulation promotes overexpression of SREBP1, enhancing lipogenesis and metastatic potential. Ketone bodies are metabolic by-products of fatty acid oxidation, used by tumor cells as an energy source to fuel rapid proliferation. Created with BioRender.com.

Figure 3

Schematic representation of the main metabolic pathways involved in cancer. The red line indicates the reduction in xanthine oxidase (XOR) expression, which is correlated with various forms of cancer. Folate, as 5-MTHF helps convert homocysteine to methionine, essential for DNA methylation. However, folate deficiency or excess can disrupt DNA repair and cell replication. Additionally, folate receptors (FR-α and FR-β) are overexpressed in many tumors. In cancer cells, purine nucleotides are synthesized via the de novo biosynthetic pathway: PRPP is generated directly to form IMP, which in turn contributes to the production of various intermediates such as AMP, GMP, and inosine. Hypoxanthine, a key purine derivative, is linked to tumor progression. Loss of xanthine oxidase (XOR) expression is related to various forms of cancer. The exDNA acts as a ligand for Toll-like receptor 9 (TLR9) and activates the NF-kB pathway, enhancing tumor-promoted inflammation. Cyclic GMP-AMP (cGAMP), synthesized in response to DNA damage, activates the STING pathway, supporting tumor inflammation. Created with BioRender.com.

Figure 4

UPR pathway. The red line indicates XBP1s. IRE1 pathway: in response to ER stress, IRE1 undergoes oligomerization and autophosphorylation, triggering the splicing of XBP1. The spliced form of XBP1 (XBP1s) acts as a transcription factor to activate genes associated with the unfolded protein response (UPR). Additionally, the RNase domain of IRE1α mediates the degradation of specific mRNAs and microRNAs through a process called IRE1α-dependent decay (RIDD). IRE1α also interacts with tumor necrosis factor receptor-associated protein (TRAF-2), resulting in the phosphorylation of c-Jun N-terminal kinase (JNK) and in the degradation of IκB, which leads to the activation of NF-κB signaling. PERK pathway: PERK phosphorylates eIF2α, which in turn stimulates ATF4. ATF4 regulates the expression of genes involved in the cellular stress response. ATF6 pathway: ATF6 is cleaved by the proteases S1P and S2P to produce its active form, ATF6f. ATF6f then translocates to the nucleus, where it initiates the transcription of genes involved in the UPR. Created with BioRender.com.