Regulation of the pentose phosphate pathway in cancer

Abstract

Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the promotion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phosphate pathway (PPP) is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxidative branch and produces a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell proliferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous factors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.

Figure 1

A schematic representation of the PPP and glycolysis is shown. The oxidative branch of the PPP yields NADPH that can be used in biosynthetic reactions for nucleotides, lipids and antioxidant defense. The reversible non-oxidative branch produces ribose-5-phosphate from oxidative branch as well as glycolytic intermediates. Solid black arrows represent glycolytic flux, green arrows represent the oxidative branch of the PPP, and light blue arrows represent multi-step processes of non-oxidative branch of PPP. For clarity, each component of the metabolic process has been abbreviated. PPP, pentose phosphate pathway; G6PD, glucose-6-phosphate dehydrogenase; 6PGD, 6-phosphogluconate dehydrogenase; TKT, transketolase; Taldo1, transaldolase; HK, hexokinase; GLUT, glucose transporters; PFK1, phosphofructokinse-1; PGM, phosphoglyceratemutase; PKM2, pyruvate kinase (PK)-M2; LDHA, lactate dehydrogenase A; FBP, fructose-1,6-bisphosphate; PEP, phosphoenolpyruvate

Figure 2

Regulation ofsome key oncoproteins and tumor suppressors on glycolysis and PPP. Tumor proteins, including PI3K and K-ras^G12D that are often activated in cancers, positively regulate glycolysis and PPP. Consistently, inactivation of tumor suppressors such as p53, PTEN or AMPK leads to enhancement of both glycolysis and PPP flux and supports cell proliferation. PI3K, phosphoinositide 3-kinase; AMPK, AMP-activated protein kinase; PTEN, phosphatase and tensin homologue; mTORC1, mTOR complex 1

Figure 3

PPP is either positively or negatively regulated by numerous factors as indicated. ATM, the ataxia-telangiectasia mutated kinase; cAMP, cyclic adenosine monophosphate; CREM, cyclic AMP-response element modulator; PKA, protein kinase A

Figure 4

Metabolic alterations of PPP flux in response to oxidative stress and genotoxic stress. Oxidative stresses reprogram PPP by oncogenic regulation through activation of TAp73 or HSP27, or by metabolic alteration of glycolysis to build up the glycolytic intermediates