Signaling Pathways Involved in Nutrient Sensing Control in Cancer Stem Cells: An Overview

Abstract

Cancer cells characteristically have a high proliferation rate. Because tumor growth depends on energy-consuming anabolic processes, including biosynthesis of protein, lipid, and nucleotides, many tumor-associated conditions, including intermittent oxygen deficiency due to insufficient vascularization, oxidative stress, and nutrient deprivation, results from fast growth. To cope with these environmental stressors, cancer cells, including cancer stem cells, must adapt their metabolism to maintain cellular homeostasis. It is well- known that cancer stem cells (CSC) reprogram their metabolism to adapt to live in hypoxic niches. They usually change from oxidative phosphorylation to increased aerobic glycolysis even in the presence of oxygen. However, as opposed to most differentiated cancer cells relying on glycolysis, CSCs can be highly glycolytic or oxidative phosphorylation-dependent, displaying high metabolic plasticity. Although the influence of the metabolic and nutrient-sensing pathways on the maintenance of stemness has been recognized, the molecular mechanisms that link these pathways to stemness are not well known. Here in this review, we describe the most relevant signaling pathways involved in nutrient sensing and cancer cell survival. Among them, Adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway, mTOR pathway, and Hexosamine Biosynthetic Pathway (HBP) are critical sensors of cellular energy and nutrient status in cancer cells and interact in complex and dynamic ways.

The metabolomic landscape plays a critical role in glioma oncogenesis

“…These data lead to the proposal that glucose and amino acid metabolism interact in mTOR‐activated cancer cells as dictated by the availability of nutrients. Apart from mTOR‐dependent nutrient sensing, the adenosine monophosphate (AMP)‐activated protein kinase (AMPK) pathway and hexosamine biosynthetic pathway (HBP)‐hypoxia‐inducible factor (HIF) axis are critical sensors of energy and nutrient status in cancer stem cells, 32 and nutrient sensing could therefore be the essential function to maximize the survival of cancer cells in various metabolic niches.…”

Genome Scale Modeling to Study the Metabolic Competition between Cells in the Tumor Microenvironment

“…Moreover, mTORC1-mediates the amino acid sensing with the help of arginine sensor proteins and the arginine level controls mTOR activity [50]. In cancer cells dysregulation of the PI3K/Akt or the Ras/ERK signaling are coupled to mTOR activation which controls differentiation, proliferation, survival, cytoskeleton organization and autophagy [51]. Other examples of metabolite sensors constitute transmembrane proteins, such as G-protein-coupled receptors, that can function as a succinate and α-ketoglutarate receptor that sense metabolites for the TCA cycle [50] which importance in oncogenesis relays in the control of cellular energy and synthesis of precursors for biosynthetic pathways [52].…”

“…AMPK is a sensor of cellular energy and nutritional status; therefore, it plays a key role in the regulation of the cell energy homeostasis and carcinogenesis as energy balance dysregulation is an important driver of the alterations in cancer [ 50 ]. Changes in AMP/ATP ratio regulate the activity of key metabolic enzymes governing anabolic and catabolic pathways that facilitate cell survival, control mitochondrial respiration, nutrient transport, autophagy, differentiation, and cell polarity [ 51 ]. An increased ratio of AMP/ATP in metabolically stressed cells enhances phosphorylation of AMPK that results in activation of ATP- producing pathways [ 21 ].…”

The Role of Metabolism in the Development of Personalized Therapies in Acute Myeloid Leukemia

“…As one example, the mTOR pathway, which is a long recognized regulator of glucose, lipid and amino acid metabolism, has been recently re-evaluated for AML treatment in combination with standard chemotherapy when given in specific timed manner ( 86 ). Due to the breadth of the field of signaling in metabolic regulation, we refer the readers to other dedicated reviews on the topic ( 85 , 87 , 88 ).…”