Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K

Abstract

Cancer cells have been shown to have altered metabolism when compared to normal non-malignant cells. The Warburg effect describes a phenomenon in which cancer cells preferentially metabolize glucose by glycolysis, producing lactate as an end product, despite being the presence of oxygen. The phenomenon was first described by Otto Warburg in the 1920s, and has resurfaced as a controversial theory, with both supportive and opposing arguments. The biochemical aspects of the Warburg effect outline a strong explanation for the cause of cancer cell proliferation, by providing the biological requirements for a cell to grow. Studies have shown that pathways such as phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) as well as hypoxia inducible factor-1 (HIF-1) are central regulators of glycolysis, cancer metabolism and cancer cell proliferation. Studies have shown that PI3K signaling pathways have a role in many cellular processes such as metabolism, inflammation, cell survival, motility and cancer progression. Herein, the cellular aspects of the PI3K pathway are described, as well as the influence HIF has on cancer cell metabolism. HIF-1 activation has been related to angiogenesis, erythropoiesis and modulation of key enzymes involved in aerobic glycolysis, thereby modulating key processes required for the Warburg effect. In this review we discuss the molecular aspects of the Warburg effect with a particular emphasis on the role of the HIF-1 and the PI3K pathway.

MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis

“…Inhibition of glycolysis has been suggested to improve the outcomes for cancer therapy (8,9). Hypoxia-inducible factor (HIF)-1, a heterodimer composed of an α and a β subunit, plays a critical role in cellular and systemic homeostatic response to hypoxia by activating transcription of many genes involved in energy metabolism, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia (10,11). Our previous study reported that HIF-1α played an oncogenic role in MM (12).…”

Silencing LDHA inhibits proliferation, induces apoptosis and increases chemosensitivity to temozolomide in glioma cells

“…Cell cycle analysis was performed using propidium iodide (PI) stain (BD Biosciences, Franklin Lakes, NJ, USA) according to the manufacturer's instructions. Briefly, U87 and U251 cells (5x10 5 ) transfected with si-NC or si-LDHA were harvested, fixed in 5 ml of ice-cold 70% ethanol overnight, and incubated with 50 µg/ml PI at 4˚C; then, the DNA content was determined using a FACSVerse flow cytometer (BD Biosciences). The percentages of cells in G0/G1, S, and G2/M phases are presented quantitatively.…”

“…The Warburg effect, also known as aerobic glycolysis, is an emerging hallmark of tumor cell metabolism (4)(5)(6). Lactate dehydrogenase A (LDHA) is a key enzyme in aerobic glycolysis that increases glucose uptake and lactate production in tumor cells; LDHA has attracted increasing attention in recent years due to its critical role in tumor progression (7)(8)(9).…”

TThe role of hypoxia-inducible factors in leukemias

“…Low oxygen levels cause the activation of mTOR kinase 1 (mTORC1) and modify tumor metabolism through the HIF signaling pathway, leading to tumor growth. 4 The role of hypoxia-inducible factors As Semenza wrote: " [HIF] transcription factors are master regulators of the cellular response to hypoxia and coordinate a transcriptional program that ensures optimal functional, metabolic, and vascular adaptation to O 2 shortages".…”