Inverse correlation between heme synthesis and the Warburg effect in cancer cells

Abstract

Abstracts 12Cancer cells show a bias toward the glycolytic system over the conventional mitochondrial 13 electron transfer system for obtaining energy. This biased metabolic adaptation is called the Warburg 14 effect. Cancer cells also exhibit a characteristic metabolism, a decreased heme synthesizing ability. Here 15 we show that heme synthesis and the Warburg effect are inversely correlated. We used human gastric 16 cancer cell lines to investigate glycolytic metabolism and electron transfer system toward 17 promotion/inhibition of heme synthesis. Under hypoxic conditions, heme synthesis was suppressed and 18 the glycolytic system was enhanced. Addition of a heme precursor for the promotion of heme synthesis 19 led to an enhanced electron transfer system and inhibited the glycolytic system and vice versa. Enhanced 20 heme synthesis leads to suppression of cancer cell proliferation by increasing intracellular reactive oxygen 21 species levels. Collectively, the promotion of heme synthesis in cancer cells eliminated the Warburg effect 22 by shifting energy metabolism from glycolysis to oxidative phosphorylation. 3 23 33 CoA, which links the glycolytic pathway and TCA cycle. Thus, HIF-1 regulates PDK-1 and functions as 34 a modulator of glycolysis and TCA cycle. Moreover, HIF-1 induces glucose transporter-1 and glycolytic 35 enzymes [6,7] and consequently leads to increased lactic acid formation. Thus, HIF-1 shifts metabolism 36 from oxidative phosphorylation to glycolysis under hypoxic conditions [8,9], thereby promoting the 37 Warburg effect under hypoxia. 38 5-Aminolevulinic acid (ALA) is a precursor in the porphyrin synthesis pathway leading to heme 39 formation [10]. The rate-limiting enzyme in heme synthesis is the mitochondrial enzyme ALA synthase 4 40 (ALAS) [11]. ALA is metabolized to protoporphyrin IX (PpIX) by multiple enzymatic reactions while 41 between cytoplasm and mitochondria, and is finally synthesized into heme by the enzyme ferrochelatase, 42 which coordinates iron ion to porphyrin [12]. Administration of ALA into tumors leads to intracellular 43 accumulation of PpIX because cancer cells exert limited ferrochelatase activity [13,14]. Hypoxia is 44 believed to induce a reduction in PpIX accumulation [15,16]. To the best of our knowledge, the influence 45 of hypoxia on heme synthesis has not yet been clarified [17,18]. 46One of the advantages of the Warburg effect is the ability to suppress cytotoxic reactive oxygen 47 6 60 Methods 61

TCGA mRNA Expression Analysis of the Heme Biosynthesis Pathway in Diffusely Infiltrating Gliomas: A Comparison of Typically 5-ALA Fluorescent and Non-Fluorescent Gliomas

“…Based on these observations we thus did not find evidence for a substantial impact of the tumor types in WHO grade II gliomas. (4) Moreover, a current study demonstrated that highly glycolytic tumors do require less heme [ 33 ]. This mechanism might result in heterogeneity of the metabolic composition of especially high-grade gliomas.…”

Surface Functionalization of Green‐synthesized Reduced Graphene Oxide with PPIX Enhances Photosensitization of Cancer Cells

“…This fluorogenic dye indicates the overall ROS production. Some studies referred this marker is able to determine the hydroxyl, peroxyl and other ROS activities within the cell (37,38). Cells treated with rGO, PPIX and PPIX + rGO were washed thoroughly with PBS after 24 h of incubation.…”

Impacts of Oxidative Stress and PI3K/AKT/mTOR on Metabolism and the Future Direction of Investigating Fucoidan-Modulated Metabolism

“…Antioxidants 2022, 11, x FOR PEER REVIEW 2 of 17 (PI3K/AKT/mTOR) are important in regulating several kinds of metabolisms in cancer cells [5][6][7][8][9][10].…”

“…Several factors that modulate metabolism may improve the anticancer therapeutic effects. Oxidative stress and phosphoinositide-3-kinase/AKT serine-threonine kinase/mechanistic target of the rapamycin kinase (PI3K/AKT/mTOR) are important in regulating several kinds of metabolisms in cancer cells [5][6][7][8][9][10].…”