Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism

Abstract

This review of the basics of cancer metabolism focuses on exploiting the metabolic differences between normal and cancer cells. The first part of the review covers the different metabolic pathways utilized in normal cells to generate cellular energy, or ATP, and the glycolytic intermediates required to build the cellular machinery. The second part of the review discusses aerobic glycolysis, or the Warburg effect, and the metabolic reprogramming involving glycolysis, tricarboxylic acid cycle, and glutaminolysis in the context of developing targeted inhibitors in cancer cells. Finally, the selective targeting of cancer mitochondrial metabolism using positively charged lipophilic compounds as potential therapeutics and their ability to mitigate the toxic side effects of conventional chemotherapeutics in normal cells are discussed. I hope this graphical review will be useful in helping undergraduate, graduate, and medical students understand how investigating the basics of cancer cell metabolism could provide new insight in developing potentially new anticancer treatment strategies.

Fig. 1

Map showing the location of Chennai in India. Chennai (formerly Madras), located on the coast of the Bay of Bengal, is the capital of the state of Tamil Nadu. Also dubbed as the “Detroit of India” due to a thriving automotive industry, the population of Chennai including the suburbs is nearly 10 million.

Fig. 2

Mitosis of normal cells – a process by which normal cells replicate in an orderly fashion.

Fig. 3

Formation of neoplasms, invasion, and metastasis of cancer cells.

Fig. 4

Cellular energy formed from metabolism of carbohydrates, proteins, and fats in normal cells.

Fig. 5

Targeting the various energetic pathways in cancer metabolism. (Modified; reprinted from Developmental Cell, 36/5, Hosios AM, Hecht VC, Danai LV, Johnson MO, Rathmell JC, Steinhauser ML, Manalis SR, Vander Heiden MG, Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells, 540-9, Copyright (2016) , with permission from Elsevier.)

Fig. 6

Metabolic differences in normal and cancer cells and tissues.

Fig. 7

The glycolytic pathway showing catabolic and anabolic intermediates and products derived from glucose.

Fig. 8

The Krebs cycle or the TCA cycle fueled by pyruvate derived from glucose and glutamine.

Fig. 9

Mitochondrial electron transport chain complexes involved in oxidative phosphorylation. (Modified from a slide obtained from Paul Brooks.)

Fig. 10

The reverse Warburg effect in cancer metabolism. (Modified from Martinez-Outschoorn UE et al., Cell Cycle, 10:4208-16, 2011 .)

Fig. 11

Lactate shuttle between tumor cells and normal cells. (Modified; republished with permission of American Society for Clinical Investigation, from Tumor Metabolism: Cancer Cells Give and Take Lactate, Gregg L. Semenza, 118, 12, 2008 ; permission conveyed through Copyright Clearance Center, Inc.)

Fig. 12

Release of fatty acid and factors controlling cancer onset. (Modified; reprinted from Cell, 140/1, Jessica L. Yecies, Brendan D. Manning, Chewing the Fat on Tumor Cell Metabolism, 28–30, Copyright (2010) , with permission from Elsevier.)

Fig. 13

Inhibitors of the glycolytic pathway. (Modified; reprinted by permission from Macmillan Publishers Ltd: Oncogene (Pelicano H et al. Ongogene 25:4633-46, 2006), copyright (2006) .)