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Caffeine Targets G6PDH to Disrupt Redox Homeostasis and Inhibit Renal Cell Carcinoma Proliferation.

ABSTRACT: Glucose-6-phosphate dehydrogenase (G6PDH) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) and plays a crucial role in the maintenance of redox homeostasis by producing nicotinamide adenine dinucleotide phosphate (NADPH), the major intracellular reductant. G6PDH has been shown to be a biomarker and potential therapeutic target for renal cell carcinoma (RCC). Here, we report a previously unknown biochemical mechanism through which caffeine, a well-known natural small molecule, regulates G6PDH activity to disrupt cellular redox homeostasis and suppress RCC development and progression. We found that caffeine can inhibit G6PDH enzymatic activity. Mechanistically, caffeine directly binds to G6PDH with high affinity (K D = 0.1923 ?M) and competes with the coenzyme NADP+ for G6PDH binding, as demonstrated by the decreased binding affinities of G6PDH for its coenzyme and substrate. Molecular docking studies revealed that caffeine binds to G6PDH at the structural NADP+ binding site, and chemical cross-linking analysis demonstrated that caffeine inhibits the formation of dimeric G6PDH. G6PDH inhibition abrogated the inhibitory effects of caffeine on RCC cell growth. Moreover, inhibition of G6PDH activity by caffeine led to a reduction in the intracellular levels of NADPH and reactive oxygen species (ROS), and altered the expression of redox-related proteins in RCC cells. Accordingly, caffeine could inhibit tumor growth through inhibition of G6PDH activity in vivo. Taken together, these results demonstrated that caffeine can target G6PDH to disrupt redox homeostasis and inhibit RCC tumor growth, and has potential as a therapeutic agent for the treatment of RCC.

SUBMITTER: Xu H

PROVIDER: S-EPMC7573228 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Caffeine Targets G6PDH to Disrupt Redox Homeostasis and Inhibit Renal Cell Carcinoma Proliferation.

Xu Huanhuan H Hu Lihong L Liu Titi T Chen Fei F Li Jin J Xu Jing J Jiang Li L Xiang Zemin Z Wang Xuanjun X Sheng Jun J

Frontiers in cell and developmental biology 20201006

Glucose-6-phosphate dehydrogenase (G6PDH) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) and plays a crucial role in the maintenance of redox homeostasis by producing nicotinamide adenine dinucleotide phosphate (NADPH), the major intracellular reductant. G6PDH has been shown to be a biomarker and potential therapeutic target for renal cell carcinoma (RCC). Here, we report a previously unknown biochemical mechanism through which caffeine, a well-known natural small molecule, r ...[more]

PMID: 33123534

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Project description:Simple Summary FOXD1 regulates the proliferation of clear cell renal cell carcinoma (ccRCC) cells, and ccRCC cells in which FOXD1 has been inactivated do not form tumors efficiently in an animal model. Reproducing growth inhibition in tumor cells by inhibiting FOXD1 pathways presents a possible therapeutic approach for ccRCC and other cancers. We have established an analysis strategy to identify FOXD1-regulated target pathways that may be therapeutically tractable, and compounds that modulate these pathways were selected for testing. Targets in three pathways were identified: FOXM1, PME1, and TMEM167A, which were inhibited by compounds FDI-6, AMZ-30, and silibinin, respectively. The effects of these compounds on the growth of tumor cells from patients cultured in a novel 3D tumor-replica culture environment revealed that FDI-6 and silibinin had strong growth inhibitory effects. This investigation informs new therapeutic targets to control ccRCC tumor growth, and provides a strategy to compare the responsiveness of individual patient tumor replicas to growth-inhibitory compounds. Abstract Clinical association studies suggest that FOXD1 is a determinant of patient outcome in clear cell renal cell carcinoma (ccRCC), and laboratory investigations have defined a role for this transcription factor in controlling the growth of tumors through regulation of the G2/M cell cycle transition. We hypothesized that the identification of pathways downstream of FOXD1 may define candidates for pharmacological modulation to suppress the G2/M transition in ccRCC. We developed an analysis pipeline that utilizes RNA sequencing, transcription factor binding site analysis, and phenotype validation to identify candidate effectors downstream from FOXD1. Compounds that modulate candidate pathways were tested for their ability to cause growth delay at G2/M. Three targets were identified: FOXM1, PME1, and TMEM167A, which were targeted by compounds FDI-6, AMZ-30, and silibinin, respectively. A 3D ccRCC tumor replica model was used to investigate the effects of these compounds on the growth of primary cells from five patients. While silibinin reduced 3D growth in a subset of tumor replicas, FDI-6 reduced growth in all. This study identifies tractable pathways to target G2/M transition and inhibit ccRCC growth, demonstrates the applicability of these strategies across patient tumor replicas, and provides a platform for individualized patient testing of compounds that inhibit tumor growth.

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Caffeine Targets G6PDH to Disrupt Redox Homeostasis and Inhibit Renal Cell Carcinoma Proliferation.

Publications

Caffeine Targets G6PDH to Disrupt Redox Homeostasis and Inhibit Renal Cell Carcinoma Proliferation.

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