6‐Phosphogluconate dehydrogenase fuels multiple aspects of cancer cells: From cancer initiation to metastasis and chemoresistance

Abstract

Reprogrammed metabolism is key biochemical characteristic of malignant cells which represents one of the emerging hallmarks of cancer. Currently, there is rising contemplation on oxidative pentose phosphate pathway (PPP) enzymes as potential therapeutic hits due to their affiliation with tumor metabolism. 6-phosphogluconate dehydrogenase (6PGD), third oxidative decarboxylase of PPP, has received a great deal of attention during recent years due to its critical role in tumorigenesis and redox homeostasis. 6PGD has been reported to overexpress in number of cancer types and its hyperactivation is mediated through post-transcriptional and posttranslational modifications by YTH domain family 2 (YTHDF2), Nrf2 (Nuclear factor erythroid 2-related factor 2), EGFR (Epidermal growth factor receptor) and via direct structural interactions with ME1 (malic enzyme 1). Up-regulated expression of 6PGD provides metabolic as well as defensive advantage to cancer cells, thus, promoting their proliferative and metastatic potential. Moreover, enhanced 6PGD expression also performs key role in development of chemoresistance as well as radiation resistance in cancer. This review aims to discuss the historical timeline and cancer-specific role of 6PGD, pharmacological and genetic inhibitors of 6PGD and 6PGD as prognostic biomarker in order to explore its potential for therapeutic interventions. We anticipate that targeting this imperative supplier of NADPH might serve as tempting avenue to combat the deadly disease like cancer.

Ferroptosis-Related Genes in Lung Adenocarcinoma: Prognostic Signature and Immune, Drug Resistance, Mutation Analysis

“…For example, PGD is highly expressed in stage IV LUAD. In addition, many previous studies have demonstrated that overexpression of PGD could lead to cancer metastasis and poor prognosis through diverse mechanisms ( Bechard et al, 2018 ; Sarfraz et al, 2020 ).…”

“…Although the association between energy metabolism and ferroptosis remains puzzling, Dubreuil et al (2020) have recently discovered that disrupting PPP by PGD knockout inhibits ROS accumulation. Besides, many previous studies have demonstrated that overexpression of PGD could lead to cancer metastasis and poor prognosis ( Bechard et al, 2018 ; Sarfraz et al, 2020 ). In our study, the alteration rate of PGD was more than 1.2% and was related to a significantly poor prognosis.…”

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

“…47,48 PGD is also hyperactive and plays a fundamental role in tumor growth. 49,50 G6PD or PGD depletion significantly decrease NADPH levels and enhance chemotherapeutic drugs-induced cell apoptosis by redox modulation. 51,52 For what concerns activity regulation, NADP + is required for G6PD enzymatic activity, whereas NADPH negatively regulates its activity.…”

Reactive Oxygen Species, Metabolic Plasticity, and Drug Resistance in Cancer

“…Furthermore, Zhang et al established that the TGFβ1-FOXM1-HMGA1-TGFβ1 positive feedback loop maintain G6PD expression in cisplatin resistant cells, and that disruption of this axis sensitizes the cells to the drug [181]. Aberrant expression of 6-phosphogluconate has also been shown to be involved in chemotherapeutic and radiation resistance [182][183][184]. Although preliminary, recent evidence has shown that epidermal growth factor receptor (EGFR) phosphorylates 6PGD at tyrosine (Y481), which enhances 6PGD activity by increasing its affinity to NAD + .…”