Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation

Ricciardiello, Francesca; Ye, Gang; Palorini, Roberta; Li, Quanxiao; Giampà, Marco; Zhao, Fangyu; You, Lei; Ferla, Barbara La; Vitto, Humberto De; Guan, Wenfang; Gu, Jin; Zhang, Taiping; Zhao, Yupei; Chiaradonna, Ferdinando

doi:10.1038/s41388-020-1260-1

Cited by 37 publications

(51 citation statements)

References 45 publications

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“…DON has also been reported to sensitize PDA cells to the chemotherapeutic gemcitabine in vitro (Chen et al, 2017). Additionally, a recently developed inhibitor targeting the HBP enzyme phosphoacetylglucosamine mutase 3 (PGM3) enhances gemcitabine-mediated reduction of xenograft tumor growth in vivo (Ricciardiello et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Glutamine deprivation triggers NAGK-dependent hexosamine salvage

Campbell

Mesaros

Affronti

et al. 2020

Preprint

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Tumors of many types exhibit aberrant glycosylation, which can impact cancer progression and therapeutic responses. The hexosamine biosynthesis pathway (HBP) branches from glycolysis at fructose-6-phosphate to synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. HBP enzyme gene expression is elevated in pancreatic ductal adenocarcinoma (PDA), and studies have pointed to the potential significance of the HBP as a therapeutic target. Yet, the PDA tumor microenvironment is nutrient poor, and adaptive nutrient acquisition strategies support tumorigenesis. Here, we identify that pancreatic cancer cells salvage GlcNAc via N-acetylglucosamine kinase (NAGK), particularly under glutamine limitation. Glutamine deprivation suppresses de novo HBP flux and triggers upregulation of NAGK. NAGK expression is elevated in human PDA. NAGK deletion forces PDA cells to rely on de novo UDP-GlcNAc synthesis and impairs tumor growth in mice. Together, these data identify an important role for NAGK-dependent hexosamine salvage in supporting PDA tumor growth.

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Section: Introductionmentioning

confidence: 99%

Glutamine deprivation triggers NAGK-dependent hexosamine salvage

Campbell

Mesaros

Affronti

et al. 2020

Preprint

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“…Of note, not a few glycoproteins were listed as downregulated proteins ( Figure 7C ), and their glycosylated forms were markedly downregulated by PT treatment (NRP1, SDC4, ITGA5; Figure 7, D and E ). Also, the oncoproteins that rely on the hexosamine pathway for its proper expression and function, such as c-Myc, EGFR, and Akt ( 23 , 24 ), were also downregulated by PT treatment ( Figure 7D ). These data suggested that the decreased levels of metabolites in the hexosamine pathway negatively affected the stability and folding of oncoproteins.…”

Section: Resultsmentioning

confidence: 99%

Petasin potently inhibits mitochondrial complex I–based metabolism that supports tumor growth and metastasis

Heishima

Sugito

Soga

et al. 2021

Journal of Clinical Investigation

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Mitochondrial electron transport chain complex I (ETCC1) is the essential core of cancer metabolism, yet potent ETCC1 inhibitors capable of safely suppressing tumor growth and metastasis in vivo are limited. From a plant extract screening, we identified petasin (PT) as a highly potent ETCC1 inhibitor with a chemical structure distinct from conventional inhibitors. PT had at least 1700 times higher activity than that of metformin or phenformin and induced cytotoxicity against a broad spectrum of tumor types. PT administration also induced prominent growth inhibition in multiple syngeneic and xenograft mouse models in vivo. Despite its higher potency, it showed no apparent toxicity toward nontumor cells and normal organs. Also, treatment with PT attenuated cellular motility and focal adhesion in vitro as well as lung metastasis in vivo. Metabolome and proteome analyses revealed that PT severely depleted the level of aspartate, disrupted tumor-associated metabolism of nucleotide synthesis and glycosylation, and downregulated major oncoproteins associated with proliferation and metastasis. These findings indicate the promising potential of PT as a potent ETCC1 inhibitor to target the metabolic vulnerability of tumor cells.

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“…The hexosamine biosynthetic pathway is a shunt pathway of glycolysis and is a metabolic node in cancer cells 39 . Studies have shown that the up‐regulation of the hexosamine biosynthetic pathway is related to tumour survival and chemotherapy resistance 40 . Inhibiting the biosynthetic pathway of hexosamine can have a significant therapeutic effect on patients with acute myeloid leukaemia 41 .…”

Section: Discussionmentioning

confidence: 99%

“… 39 Studies have shown that the up‐regulation of the hexosamine biosynthetic pathway is related to tumour survival and chemotherapy resistance. 40 Inhibiting the biosynthetic pathway of hexosamine can have a significant therapeutic effect on patients with acute myeloid leukaemia. 41 A recent study showed that targeting endogenous hexosamine biosynthesis makes pancreatic cancer sensitive to anti‐PD1 treatment.…”

Section: Discussionmentioning

confidence: 99%

Signature based on metabolic‐related gene pairs can predict overall survival of osteosarcoma patients

Zhang

Yuan

et al. 2021

Cancer Medicine

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Background Osteosarcoma is a tumour of malignant origin in children and adolescents. Recent progression indicates that it is necessary to develop new therapies to improve the patient's prognosis rather than strengthen anti‐tumour chemotherapy. Researchers recently realised that cancer is a kind of disease with a metabolic disorder, and metabolic reprogramming is becoming a new cancer hallmark. Hence, our study's primary purpose is to explore the value of genes related to osteosarcoma metabolism. Methods From public databases, three osteosarcoma datasets with adequate clinical information were obtained. Besides, the IMvigor dataset through the ‘IMvigor’ package as a supplement was downloaded, the metabolic‐related genes were identified, and these genes were used to construct the metabolic‐related gene pairs (MRGP). Based on the prognosis‐related MRGP, two molecular subtypes were identified. There are significant differences in the metabolic characteristics between the two molecular subtypes. Subsequently, the MRGP signature is constructed using the least absolute shrinkage and selection operator regression method. Finally, use SubMap analysis to evaluate the response of patients in the MRPG signature group to immunotherapy. Results The MRGP signature can reliably predict overall survival in patients with osteosarcoma. The MRGP signature is also associated with osteosarcoma patients’ metastatic status and can be used for subsequent risk classification of metastatic patients. The immunotherapy is more likely to benefit the patients in the MRGP low‐risk group. Conclusion Metabolic‐related gene pairs signature can assess the prognosis of patients with osteosarcoma.

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Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation

Cited by 37 publications

References 45 publications

Glutamine deprivation triggers NAGK-dependent hexosamine salvage

Glutamine deprivation triggers NAGK-dependent hexosamine salvage

Petasin potently inhibits mitochondrial complex I–based metabolism that supports tumor growth and metastasis

Signature based on metabolic‐related gene pairs can predict overall survival of osteosarcoma patients

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