The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH

Abstract

The Pentose Phosphate Pathway (PPP) is one of the key metabolic pathways occurring in living cells to produce energy and maintain cellular homeostasis. Cancer cells have higher cytoplasmic utilization of glucose (glycolysis), even in the presence of oxygen; this is known as the “Warburg Effect”. However, cytoplasmic glucose utilization can also occur in cancer through the PPP. This pathway contributes to cancer cells by operating in many different ways: (i) as a defense mechanism via the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) to prevent apoptosis, (ii) as a provision for the maintenance of energy by intermediate glycolysis, (iii) by increasing genomic material to the cellular pool of nucleic acid bases, (iv) by promoting survival through increasing glycolysis, and so increasing acid production, and (v) by inducing cellular proliferation by the synthesis of nucleic acid, fatty acid, and amino acid. Each step of the PPP can be upregulated in some types of cancer but not in others. An interesting aspect of this metabolic pathway is the shared regulation of the glycolytic and PPP pathways by intracellular pH (pHi). Indeed, as with glycolysis, the optimum activity of the enzymes driving the PPP occurs at an alkaline pHi, which is compatible with the cytoplasmic pH of cancer cells. Here, we outline each step of the PPP and discuss its possible correlation with cancer.

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

“…This reduction is compensated by the accelerated cytosolic conversion of ADP to ATP that accompanies the elevated glycolysis [ 120 , 121 ]. Additionally, to support the high synthetic requirements of cells that adopt the Warburg-type metabolism, they employ the pentose phosphate pathway (PPP) [ 122 ] ( Figure 4 ). This pathway is initiated when glucose-6-phosphate is enzymatically converted to glucose-1,5-lactone 6P by the glucose-6-phosphate dehydrogenase; this is the rate limiting step in the PPP and the pathway yields 2 mol NADPH and CO 2 .…”

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…The pHi alkalinity results in the upregulation of the utilization of glucose (Glycolysis + Pentose Phosphate Pathway), while it slows down the Krebs cycle [ 7 , 28 ]. Therefore, NHE1 over-expression reprograms the metabolic cell machinery to undergo Warburg metabolism and produce lactate, which is translocated extracellularly, creating an interstitial acidity that stimulates the already diseased tumor milieu [ 40 ].…”

“…The model described here considers all aspects of malignancy from one single and integral perspective in order to embrace a wide array of apparently unrelated factors involved in the etiopathogenesis of BC [ 4 ]. This approach, based upon the cancer-selective and deregulated proton (H + ) dynamics in cancer, allows us to reach a new and deeper understanding of the intimate energetics of the acid–base dynamic nature of any malignant process, as well as of human neurodegenerative diseases (HNDDs), the latter as a beneficial side effect of the H + -related outreaching paradigm [ 4 , 5 , 6 , 7 , 8 ].…”

Cancer and pH Dynamics: Transcriptional Regulation, Proteostasis, and the Need for New Molecular Tools

“…These pH-associated cancer cell behaviors have been summarized in several recent review articles [ 16 , 17 , 18 ]. Furthermore, the roles for pHi dynamics in cancer-associated metabolic changes have been extensively covered in recent review article [ 19 , 20 , 21 ]. However, the molecular mechanisms underlying these pH-dependent cancer-associated cell behaviors are largely unknown.…”