The Pentose Phosphate Pathway in Cancer: Regulation and Therapeutic Opportunities

Abstract

<b><i>Background:</i></b> Tumorigenesis is associated with deregulation of nutritional requirements, intermediary metabolites production, and microenvironment interactions. Unlike their normal cell counterparts, tumor cells rely on aerobic glycolysis, through the Warburg effect. <b><i>Summary:</i></b> The pentose phosphate pathway (PPP) is a major glucose metabolic shunt that is upregulated in cancer cells. The PPP comprises an oxidative and a nonoxidative phase and is essential for nucleotide synthesis of rapidly dividing cells. The PPP also generates nicotinamide adenine dinucleotide phosphate, which is required for reductive metabolism and to counteract oxidative stress in tumor cells. This article reviews the regulation of the PPP and discusses inhibitors that target its main pathways. <b><i>Key Message:</i></b> Exploiting the metabolic vulnerability of the PPP offers potential novel therapeutic opportunities and improves patients’ response to cancer therapy.

S100A11 activates the pentose phosphate pathway to induce malignant biological behaviour of pancreatic ductal adenocarcinoma

“…The PPP, as a branch of glycolysis for maintaining biosynthesis and controlling redox homoeostasis, is a fundamental component of cellular metabolism [ 5 , 6 ]. It has been reported that enhanced activity of the PPP provides materials for anabolism like pentose phosphates, to use their high rate of biosynthesis, including DNA synthesis, which is considered to be critical for tumour progression and drug resistance [ 5 , 31 – 34 ].…”

“…The pentose phosphate pathway (PPP), as a committed step of glucose metabolism, which is required for maintaining the cellular redox state. Cancer cells modulate the flux of the PPP depending on the particular metabolic demand [ 5 , 6 ]. Activated PPP generates high levels of NADPH and ribonucleotides in cancer cells, which promotes pancreatic tumorigenesis and metastasis [ 7 – 9 ], emphasising the vital role of PPP in pancreatic cancer development.…”

Sedoheptulose Kinase SHPK Expression in Glioblastoma: Emerging Role of the Nonoxidative Pentose Phosphate Pathway in Tumor Proliferation

“…GBM cells are characterized by a preference for aerobic glycolysis rather than oxidative phosphorylation, which is more active in normal cells [ 33 , 34 ]. However, in addition to elevated glycolysis, proliferating and cancer cells must also divert carbon from glycolysis to the pentose phosphate pathway (PPP) to satisfy their anabolic demands and maintain the redox homeostasis of cells [ 21 ].…”

“…Although the oxidative branch of the PPP has already been studied in GBM by correlating enzyme expression with tumor aggressiveness and patient survival and proposing their targeting as a promising therapeutic target, the nonoxidative branch of the PPP has never been sufficiently evaluated in GBM. However, there are studies on other cancer types that confer an important role in tumor progression on the nonoxidative branch of the PPP and overexpression of its enzymes mainly due to increased proliferation of cancer cells [ 15 , 21 , 34 , 44 , 45 , 46 ].…”

Identification and validation of PGLS as a metabolic target for early screening and prognostic monitoring of gastric cancer

“…In normal cells, pentose phosphate pathway (PPP) has fundamental functions which were essential for cell nutrients metabolism and macromolecular biosynthesis. 15 , 16 , 17 , 18 , 19 First of all, PPP pathway generates ribulose‐5‐phosphate for nucleotide biosynthesis. Seconds, PPP pathway generates numerous NADPH, which is involved in macromolecular synthesis.…”