MTAP Deficiency–Induced Metabolic Reprogramming Creates a Vulnerability to Cotargeting <i>De Novo</i> Purine Synthesis and Glycolysis in Pancreatic Cancer

Hu, Qiangsheng; Qin, Yi; Ji, Shunrong; Shi, Xiuhui; Dai, Weixing; Fan, Guixiong; Li, Shuo; Xu, Wenyan; Liu, Wensheng; Liu, Mengqi; Zhang, Zheng; Zeng, Ye; Zhou, Zhijun; Yang, Jingxuan; Zhuo, Qifeng; Lei, Yu; Li, Min; Xu, Xiaowu

doi:10.1158/0008-5472.can-20-0414

Cited by 19 publications

(9 citation statements)

References 62 publications

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“…54 More recently, we found that a key enzyme related to the salvage of methionine and adenine, methylthioadenosine phosphorylase (MTAP) is deficient in 20%-30% of pancreatic cancer and metabolic reprogramming mediated by its deletion enhances glycolysis and de novo synthesis of purines in pancreatic cancer cells, resulting in a poor prognosis for pancreatic cancer patients. 55 These findings reflect the important role of glycolytic upregulation caused by metabolic reprogramming in the development and progression of pancreatic cancer. Moreover, recent studies have further explored and explained the complex metabolic changes and their pattern in the tumour microenvironment and turned the spotlight to lactate, the product of glycolysis.…”

Section: Metabolic Reprogramming During Cancer Developmentmentioning

confidence: 76%

Lactate‐induced protein lactylation: A bridge between epigenetics and metabolic reprogramming in cancer

Wang

Zeng

et al. 2023

Cell Proliferation

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Lactate is not only an endpoint of glycolysis but is gradually being discovered to play the role of a universal metabolic fuel for energy via the ‘lactate shuttle’ moving between cells and transmitting signals. The glycolytic‐dependent metabolism found in tumours and fast‐growing cells has made lactate a pivotal player in energy metabolism reprogramming, which enables cells to obtain abundant energy in a short time. Moreover, lactate can provide favourable conditions for tumorigenesis by shaping the acidic tumour microenvironment, recruiting immune cells, etc. and the recently discovered lactate‐induced lactylation moves even further on pro‐tumorigenesis mechanisms of lactate production, circulation and utilization. As with other epigenetic modifications, lactylation can modify histone proteins to alter the spatial configuration of chromatin, affect DNA accessibility and regulate the expression of corresponding genes. What's more, the degree of lactylation is inseparable from the spatialized lactate concentration, which builds a bridge between epigenetics and metabolic reprogramming. Here, we review the important role of lactate in energy reprogramming, summarize the latest finding of lactylation in tumorigenesis and try to explore therapeutic strategies in oncotherapy that can kill two birds with one stone.

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Section: Metabolic Reprogramming During Cancer Developmentmentioning

confidence: 76%

Lactate‐induced protein lactylation: A bridge between epigenetics and metabolic reprogramming in cancer

Wang

Zeng

et al. 2023

Cell Proliferation

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“…Metabolic analysis showed that curcumin significantly reduced the rate of intracellular ATP production under hypoxic conditions ( 19 - 22 ). Incubation with curcumin increased the expression of PHD and a corresponding increase in hydroxylation of HIF - 1α was observed in pancreatic cancer cells exposed to hypoxic conditions ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Curcumin inhibits pancreatic cancer cell proliferation by regulating Beclin1 expression and inhibiting the hypoxia-inducible factor-1α-mediated glycolytic pathway

Guo¹,

Ding²,

Pu³

et al. 2022

J Gastrointest Oncol

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Background: Pancreatic cancer has a high degree of malignancy and high mortality. Understanding its biological status can provide more therapeutic targets for the future. The present study was to investigate whether curcumin can inhibit pancreatic cancer cell proliferation by regulating Beclin1 expression and inhibiting the hypoxia-inducible factor-1α (HIF-1α)-mediated glycolytic pathway.Methods: Two pancreatic cancer cell lines, PANC-1 and SW1990, were treated with different concentrations of curcumin (0, 20, 40, and 60 μM). Cell viability was detected using the Cell Counting Kit-8 (CCK-8) assay and flow cytometry was performed to determine the apoptosis rate and cell cycle arrest of the pancreatic cancer cells. PANC-1 and SW1990 cells were treated with different concentrations of curcumin under hypoxic conditions for 48 hours to detect the relative expression of the Beclin1 protein. The coimmunoprecipitation (co-IP) method was used to determine whether curcumin could inhibit the interaction between Beclin1 and HIF-1α.Results: The proliferation inhibition rates of PANC-1 cells after exposure to 0, 20, 40, and 60 μM curcumin were 0%, 31.6%, 47.2%, and 63.9%, respectively, and that of SW1990 cells were 0%, 18.8%, 46.3%, and 63.5% respectively. Western blot analyses showed decreased expression of Beclin1 in cells treated with curcumin. The expression of Beclin1 in the nucleus and cytoplasm decreased with increasing concentrations of curcumin. Co-IP results demonstrated that curcumin inhibited the interaction between Beclin1 and HIF-1α. Treatment with the higher doses of curcumin (40 and 60 μM) significantly decreased the protein expression levels of HIF-1α. In addition, the expression levels of Kidney-Specific Cadherin (HSP70, HSP90, and von Hippel-Lindau protein (pVHL) were significantly decreased in pancreatic cancer cells while the expression of prolyl hydroxylase (PHD) and receptor of activated protein kinase C (RACK1) increased significantly. Furthermore, curcumin reduced cellular ATP production in a dose-dependent manner. Compared with control pancreatic cancer cells, the expression levels of GLUT1, HK2, LDHA, and PDK1 gradually decreased with increasing curcumin concentrations.Conclusions: Curcumin can inhibit the expression of Beclin1 and HIF-1α in pancreatic cancer cells under anoxic conditions, thereby affecting the glycolysis pathway and inhibiting cell proliferation.

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“…RIO kinase 1 (RIOK1), a kinase upregulated in MTAP-deleted pancreatic tumor cells, could interact with and phosphorylate HIF1α to affect its stability. Glycolysis inhibitor 2-deoxy-d-glucose (2-DG) and purine synthesis inhibitor l-alanosine could synergistically exert anti-tumor effect on MTAP-deficient pancreatic cancer cells ( Hu et al, 2021 ). Pancreatic cancer organoids were also used to verify that PRMT5 inhibition effectively targets MTAP-deficient tumors.…”

Section: Mtap and Pancreatic Cancermentioning

confidence: 99%

Methylthioadenosine phosphorylase deficiency in tumors: A compelling therapeutic target

Ning

Zhang

Zou

2023

Front. Cell Dev. Biol.

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The methionine salvage pathway is responsible for recycling sulfur-containing metabolites to methionine. This salvage pathway has been found to be implicated in cell apoptosis, proliferation, differentiation and inflammatory response. Methylthioadenosine phosphorylase (MTAP) catalyzes the reversible phosphorolysis of 5′-methylthioadenosine, a by-product produced from polyamine biosynthesis. The MTAP gene is located adjacent to the cyclin-dependent kinase inhibitor 2A gene and co-deletes with CDKN2A in nearly 15% of tumors. Moreover, MTAP-deleted tumor cells exhibit greater sensitivity to methionine depletion and to the inhibitors of purine synthesis. In this review, we first summarized the molecular structure and expression of MTAP in tumors. Furthermore, we discussed PRMT5 and MAT2A as a potential vulnerability for MTAP-deleted tumors. The complex and dynamic role of MTAP in diverse malignancies has also been discussed. Finally, we demonstrated the implications for the treatment of MTAP-deleted tumors.

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MTAP Deficiency–Induced Metabolic Reprogramming Creates a Vulnerability to Cotargeting De Novo Purine Synthesis and Glycolysis in Pancreatic Cancer

Cited by 19 publications

References 62 publications

Lactate‐induced protein lactylation: A bridge between epigenetics and metabolic reprogramming in cancer

Lactate‐induced protein lactylation: A bridge between epigenetics and metabolic reprogramming in cancer

Curcumin inhibits pancreatic cancer cell proliferation by regulating Beclin1 expression and inhibiting the hypoxia-inducible factor-1α-mediated glycolytic pathway

Methylthioadenosine phosphorylase deficiency in tumors: A compelling therapeutic target

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