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, phosphatidyl-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.

Molecular Crosstalk Between MYC and HIF in Cancer

“…Similar to MYC, HIF1 is also a driver for metabolic switch from oxidative to glycolysis by upregulating glucose transporters and most glycolytic enzymes such as HK II, phosphofructokinase 1 (PFK1), fructose-bisphosphate aldolase A (ALDOA), ENO1, PKM2, and LDHA, as well as pentose phosphate pathway (PPP) enzymes (Iyer et al, 1998;Mathupala et al, 2001;Kim et al, 2006;Papandreou et al, 2006;Moldogazieva et al, 2020). In contrast to MYC, both HIF1 and HIF2 inhibit mitochondrial biogenesis in response to hypoxia.…”

Current Understanding of the HIF-1-Dependent Metabolism in Oral Squamous Cell Carcinoma

“…Despite the fact that the shift from oxidative phosphorylation (OXPHOS) to glycolysis, also called ‘glycolytic’ shift, is a crucial hallmark of oral cancer [ 41 ], tumors exhibit a great heterogeneity and cancer cells could reverse from glycolysis to OXPHOS, thereby maintaining both reprogrammed and oxidative metabolism in the same tumor [ 41 ]. This general phenomenon, called cancer cell metabolic plasticity, is a consequence of a highly heterogeneous TME influenced by diverse factors, such as oxygen concentration, nutrient and energy supply and the extent of vascularization and blood flow.…”

Role of hypoxia inducible factor-1 in cancer stem cells (Review)

“…It is commonly known that cancer cells can metabolize and reprogram under hypoxic conditions to complete the conversion of oxidative phosphorylation (OXPHOS) to glycolysis to meet their own energy needs (7,115). However, a study recently proposed the concept of metabolic plasticity, that is, even within the same cancer cell population, cancer cells can complete the conversion of glycolysis to OXPHOS, while maintaining metabolic reprogramming and energy requirements (116). Indeed, hypoxic cells do not metabolize all glucose to lactic acid, and non-hypoxic cells do not metabolize all glucose to carbon dioxide and water, which makes metabolic balance particularly important (117).…”