Glycometabolic rearrangements--aerobic glycolysis in pancreatic cancer: causes, characteristics and clinical applications

Cao, Lidong; Wu, Jiacheng; Qu, Xianzhi; Sheng, Jiyao; Cui, Mengying; Shui, Lingling; Huang, Xu; Xiang, Yien; Li, Bingjin; Zhang, Xuewen; Cui, Ranji

doi:10.1186/s13046-020-01765-x

Cited by 49 publications

(37 citation statements)

References 209 publications

(279 reference statements)

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“…For example, PDA cancer-associated fibroblasts with a glycolytic phenotype supported oxidative phosphorylation in cancer cells and, consequently, tumor survival and invasive ability [ 196 ]. The same phenomenon was observed in PDA pancreatic stellate cells via HK2 expression [ 195 , 197 ]. One of the mechanisms of the metabolic interaction of stromal and tumoral cells is through the lactate efflux, thus lactate transporters may play a pivotal role [ 198 ].…”

Section: Metabolic Reprogramming To Increase the Immune Response supporting

confidence: 69%

“…Several reports have shown that targeting the glycolytic pathway can effectively counteract tumor progression, which could also be due to the role of cells that are part of the TME. Increasing needs of nutrients and glucose in tumors could shift immune cells ( Figure 2 ) and stromal cells towards glycolytic behavior [ 195 ]. For example, PDA cancer-associated fibroblasts with a glycolytic phenotype supported oxidative phosphorylation in cancer cells and, consequently, tumor survival and invasive ability [ 196 ].…”

Section: Metabolic Reprogramming To Increase the Immune Response mentioning

confidence: 99%

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The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

et al. 2021

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Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism—resulting in its increased uptake—and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies.

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Section: Metabolic Reprogramming To Increase the Immune Response supporting

confidence: 69%

Section: Metabolic Reprogramming To Increase the Immune Response mentioning

confidence: 99%

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

et al. 2021

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“…Consistently, Pyruvate treatment reduced the ability of CK to inhibit p‐AKT, p‐mTOR, HK2, and pro‐Cas3 in treated HepG2 cells, strongly indicating that apoptotic effect of CK is closely related to energy depletion in HepG2 cells. Phosphorylation of Akt/mTOR promotes the transportation of glucose and activity of glycolytic enzymes in cancer cells (Cao et al, 2020; Hoxhaj & Manning, 2020). Upregulation of glycolysis enzymes enhances glucose consumption and lactate production (Burns & Manda, 2017; Yu, Chen, Wang, & Chen, 2016).…”

Section: Discussionmentioning

confidence: 99%

Apoptotic effect of compound K in hepatocellular carcinoma cells via inhibition of glycolysis and Akt/mTOR/c‐Myc signaling

Shin

Lee

Sim

et al. 2021

Phytotherapy Research

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Since the AKT/mammalian target of rapamycin (mTOR)/c-Myc signaling plays a pivotal role in the modulation of aerobic glycolysis and tumor growth, in the present study, the role of AKT/mTOR/c-Myc signaling in the apoptotic effect of Compound K (CK), an active ginseng saponin metabolite, was explored in HepG2 and Huh7 human hepatocellular carcinoma cells (HCCs). Here, CK exerted significant cytotoxicity, increased sub-G1, and attenuated the expression of pro-Poly (ADPribose) polymerase (pro-PARP) and Pro-cysteine aspartyl-specific protease (pro-caspase3) in HepG2 and Huh7 cells. Consistently, CK suppressed AKT/mTOR/ c-Myc and their downstreams such as Hexokinase 2 (HK2) and pyruvate kinase isozymes M2 (PKM2) in HepG2 and Huh7 cells. Additionally, CK reduced c-Myc stability in the presence or absence of cycloheximide in HepG2 cells. Furthermore, AKT inhibitor LY294002 blocked the expression of p-AKT, c-Myc, HK2, PKM2, and pro-cas3 in HepG2 cells. Pyruvate blocked the ability of CK to inhibit p-AKT, p-mTOR, HK2, and pro-Cas3 in treated HepG2 cells. Overall, these findings provide evidence that CK induces apoptosis via inhibition of glycolysis and AKT/mTOR/c-Myc signaling in HCC cells as a potent anticancer candidate for liver cancer clinical translation.

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“…Thus, these metabolite profiles could help to distinguish PDAC severity. In PDAC cells, there is an increased uptake of glucose to produce lactate and ATP under aerobic conditions, a phenomenon known as the Warburg effect [37]. Warburg effect promotes PDAC progression by providing a constant energy source for cellular growth and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Serum Metabolomic and Lipoprotein Profiling of Pancreatic Ductal Adenocarcinoma Patients of African Ancestry

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a characteristic dysregulated metabolism. Abnormal clinicopathological features linked to defective metabolic and inflammatory response pathways can induce PDAC development and progression. In this study, we investigated the metabolites and lipoproteins profiles of PDAC patients of African ancestry. Nuclear Magnetic Resonance (NMR) spectroscopy was conducted on serum obtained from consenting individuals (34 PDAC, 6 Chronic Pancreatitis, and 6 healthy participants). Seventy-five signals were quantified from each NMR spectrum. The Liposcale test was used for lipoprotein characterization. Spearman’s correlation and Kapan Meier tests were conducted for correlation and survival analyses, respectively. In our patient cohort, the results demonstrated that levels of metabolites involved in the glycolytic pathway increased with the tumour stage. Raised ethanol and 3-hydroxybutyrate were independently correlated with a shorter patient survival time, irrespective of tumour stage. Furthermore, increased levels of bilirubin resulted in an abnormal lipoprotein profile in PDAC patients. Additionally, we observed that the levels of a panel of metabolites (such as glucose and lactate) and lipoproteins correlated with those of inflammatory markers. Taken together, the metabolic phenotype can help distinguish PDAC severity and be used to predict patient survival and inform treatment intervention.

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Glycometabolic rearrangements--aerobic glycolysis in pancreatic cancer: causes, characteristics and clinical applications

Cited by 49 publications

References 209 publications

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

Apoptotic effect of compound K in hepatocellular carcinoma cells via inhibition of glycolysis and Akt/mTOR/c‐Myc signaling

Serum Metabolomic and Lipoprotein Profiling of Pancreatic Ductal Adenocarcinoma Patients of African Ancestry

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