How do cancer cells replenish their fuel supply?

Abstract

Background: Multiple genetic changes, availability of cellular nutrients and metabolic alterations play a pivotal role in oncogenesis AIMS: We focus on cancer cell's metabolic properties, and we outline the cross talks between cellular oncogenic growth pathways in cancer metabolism. The review also provides a synopsis of the relevant cancer drugs targeting metabolic activities that are at various stages of clinical development.

Methods: We review literature published within the last decade to include select articles that have highlighted energy metabolism crucial to the development of cancer phenotypes.

Results: Cancer cells maintain their potent metabolism and keep a balanced redox status by enhancing glycolysis and autophagy and rerouting Krebs cycle intermediates and products of β-oxydation.

Conclusions: The processes underlying cancer pathogenesis are extremely complex and remain elusive. The new field of systems biology provides a mathematical framework in which these homeostatic dysregulation principles may be examined for better understanding of cancer phenotypes. Knowledge of key players in cancer-related metabolic reprograming may pave the way for new therapeutic metabolism-targeted drugs and ultimately improve patient care.

Keywords: cancer metabolism; glutaminolysis; glycolysis; growth factors; mitochondrial transmembrane potential; systems biology.

Figure 1

Normal and cancer cell functions. Physiologic functions are colored in blue. Upregulated functions are colored in red and are critical for cancer cell survival. Normally, the mitochondrial transmembrane potential (Δψ) is polarized (negative inside). In cancer cells, the Δψ is more hyperpolarized than normal cells. Akt, aphakia mouse T‐cell lymphoma; AMPK, adenosine monophosphate–activated protein kinase; CpG, cytidine phosphate guanosine; HIF1‐α, hypoxia inducible factor; K‐Ras, Kisten rat sarcoma (oncogene); mTOR, mammalian target of rapamycine; Myc, myelocytomatosis (oncogene); NAD⁺, nicotinamide adenine dinucleotide; NFκB, nuclear factor kappa B; PI3k, phosphatidylinositol 3 kinase; ROS, reactive oxygen species; SDH, succinate dehydrogenase; TCA, tricarboxylic acid; Tp‐53, tumor protein 53

Figure 2

A simplified block diagram of signaling pathways by key regulators: AMPK and mTORC1. Blue arrow line means activation. Red arrow line means inhibition. These are not necessarily direct. Both, AMPK and mTORC1 are activated by the addition of amino acids. AMPK opposes mTORC1 and activates autophagy. AMP, adenosine monophosphate; AMPK, AMP‐activated protein kinase; NAD⁺, nicotinamide adenine dinucleotide; mTORC1, mammalian target of rapamycin complex 1; HIF1α, hypoxia inducible factor