Regulation of Hypoxia Dependent Reprogramming of Cancer Metabolism: Role of HIF-1 and Its Potential Therapeutic Implications in Leukemia

Abstract

Metabolic reprogramming occurs to meet cancer cells' high energy demand. Its function is essential to the survival of malignancies. Comparing cancer cells to non-malignant cells has revealed that cancer cells have altered metabolism. Several pathways, particularly mTOR, Akt, PI3K, and HIF-1 (hypoxia-inducible factor-1) modulate the metabolism of cancer. Among other aspects of cancer biology, gene expression in metabolism, survival, invasion, proliferation, and angiogenesis of cells are controlled by HIF-1, a vital controller of cellular responsiveness to hypoxia. This article examines various cancer cell metabolisms, metabolic alterations that can take place in cancer cells, metabolic pathways, and molecular aspects of metabolic alteration in cancer cells placing special attention on the consequences of hypoxia-inducible factor and summarising some of their novel targets in the treatment of cancer including leukemia. A brief description of HIF-1α's role and target in a few common types of hematological malignancies (leukemia) is also elucidated in the present article.

Keywords: Cancer Cell Metabolism; Hematological malignancies; Hypoxia-Inducible Factor-1 (HIF-1); Metabolic Reprogramming; cancer therapeutics.

Figure 1

Glucose Metabolism is an Essential Process for Every Animal Cell. The end product of complete mitochondrial respiration in humans may be lactate or CO₂ under normal circumstances, but the "Warburg Effect" refers to a situation in which glucose uptake dramatically increases and lactate production begins despite the presence of oxygen and fully functional mitochondria

Figure 2

HIF-1 Targeted Regulation of Cancer Metabolism: By stimulating the expression of glucose transporters (GLUTs) and other enzymes involved in glycolysis, HIF-1 controls a wide range of metabolic changes brought on by hypoxia. This stimulates glycolysis and results in higher amounts of pyruvate. HIF-1 also encourages pyruvate conversion to lactate by triggering lactate dehydrogenase (LDH). Pyruvate conversion to lactate regenerates NAD+, enabling hypoxic cells to carry on with glycolysis and ATP synthesis. Moreover, Pyruvate dehydrogenase kinase (PDK) is activated by HIF-1, which prevents pyruvate from being converted to acetyl CoA, hence reducing Kreb cycle flux. The reduction of oxidative phosphorylation and the excessive production of mitochondrial reactive oxygen species are caused by decreased Kreb cycle activity (ROS). The induction of PDK1 reduces the persistence of potentially hazardous ROS levels because hypoxia cells already exhibit elevated ROS, which has been shown to enhance HIF-1 accumulation. By Controlling medium-chain acyl-CoA dehydrogenase and long-chain acyl-CoA dehydrogenase, HIF-1 prevents the breakdown of fatty acids in the regulation of lipid metabolism. This causes the accumulation of fatty acids and the decrease of ROS levels, which blunts the expression of PTEN and encourages the growth of cancerous cells