Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Abstract

It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatydyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs.

Keywords: AMPK; GLUTs; HIF-1; OXPHOS; cancer metabolism.

Figure 1

Regulation of metabolic reprogramming in cancer cells. Hypoxia-inducible factor-1 (HIF-1) induces expression of genes, which encode glucose transporters, GLUT1 and GLUT3, enzymes of glycolysis and pentose-phosphate pathway, and pyruvate dehydrogenase complex kinase. Activity of HIF-1 is regulated by Ras-protein kinase B (PKB)/Akt-mammalian target of rapamycin (mTOR) axis.

Figure 2

Oxidative metabolism, oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) generation. NADH is mainly produced by glycolysis, pyruvate decarboxylase complex (PDC), fatty acid β-oxidation (FAO), and tricarboxylic acid (TCA) cycle to fuel electron transportation chain (ETC) via complex I, whereas FADH₂ is mainly produced by FAO and TCA cycle and fuels ETC via complex III. Glycerol-phosphate and malate-aspartate shuttle mechanisms serve to transfer reducing equivalents through the outer mitochondrial membrane from the cytoplasm to ETC. Superoxide anion radical, a primary type of ROS, is produced as a byproduct of ETC.

Figure 3

Interplay between AMPK-, HIF-1-, and ROS-regulated growth factor/nutrient and energy stress/hypoxia-initiated cell signaling pathways in controlling both glycolysis and OXPHOS to produce ATP for cancer cell proliferation, invasion, and migration. The involvement of AMPK in lysosomal complex formation is also shown.