O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis

Taparra, Kekoa; Wang, Hailun; Malek, Reem; Lafargue, Audrey; Barbhuiya, Mustafa A.; Wang, Xing; Simons, Brian W.; Ballew, Matthew; Nugent, Katriana; Groves, Jennifer; Williams, Russell D.; Shiraishi, Takeshi; Verdone, James E.; Yildirir, Gokben; Henry, Roger; Zhang, Bin; Wong, John W.; Wang, Ken Kang Hsin; Nelkin, Barry D.; Pienta, Kenneth J.; Felsher, Dean W.; Zachara, Natasha E.; Tran, Phuoc T.

doi:10.1172/jci94844

Cited by 54 publications

(41 citation statements)

References 53 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reason for this isoform specificity is unknown, but may involve its association with the epithelial-mesenchymal transition (EMT). EMT transcription factors SNAI1 and TWIST1 are highly correlated with GFPT2 , but not GFPT1 , in clinical lung adenocarcinoma samples 32 . Upregulation of GFPT2 expression was observed in transcriptomic signatures of both mesenchymal lung tumors in mice and the mesenchymal, or claudin-low, subtype of triple-negative breast cancer 13,32 .…”

Section: Discussionmentioning

confidence: 91%

“…EMT transcription factors SNAI1 and TWIST1 are highly correlated with GFPT2 , but not GFPT1 , in clinical lung adenocarcinoma samples 32 . Upregulation of GFPT2 expression was observed in transcriptomic signatures of both mesenchymal lung tumors in mice and the mesenchymal, or claudin-low, subtype of triple-negative breast cancer 13,32 . Given that KL co-mutants emulate claudin-low breast cancer, which are aggressively metastatic tumors enriched with self-renewing tumor-initiating cells 33 , and that GFPT2 , not GFPT1 , is one of the 10 upregulated, claudin-low signature genes found in KL NSCLC 13 , our current findings imply that GFPT2, not GFPT1, is associated with tumor aggressiveness in lung cancer.…”

Section: Discussionmentioning

confidence: 91%

See 1 more Smart Citation

The hexosamine biosynthesis pathway is a targetable liability in lung cancers with concurrent KRAS and LKB1 mutations

Cai

et al. 2020

Preprint

View full text Add to dashboard Cite

In non–small cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and the tumor suppressor STK11 encoding the kinase LKB1 result in aggressive tumors prone to metastasis but with liabilities arising from reprogrammed metabolism. We previously demonstrated perturbed nitrogen metabolism and addiction to an unconventional pathway of pyrimidine synthesis in KRAS/LKB1 co-mutant (KL) cancer cells. To gain broader insight into metabolic reprogramming in NSCLC, we analyzed tumor metabolomes in a series of genetically engineered mouse models with oncogenic KRAS combined with mutations in LKB1 or p53. Metabolomics and gene expression profiling pointed towards an activation of the hexosamine biosynthesis pathway (HBP), another nitrogen-related metabolic pathway, in both mouse and human KL mutant tumors. KL cells contain high levels of HBP metabolites, higher flux through the HBP pathway and elevated dependence on the HBP enzyme Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2). GFPT2 inhibition selectively reduced KL cell growth in culture and xenografts. Our results define a new metabolic vulnerability in KL tumors and provide a rationale for targeting GFPT2 in this aggressive NSCLC subtype.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 91%

The hexosamine biosynthesis pathway is a targetable liability in lung cancers with concurrent KRAS and LKB1 mutations

Cai

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…This pathway has been described as a sensor of nutrient availability that stimulates cancer cell growth and proliferation when the abundance of glucose and other nutrients in the microenvironment allow it [ 32 ]. The hexosamine biosynthetic pathway is required for Kras-induced transformation [ 33 ], and increased hexosamine biosynthetic pathway has been associated with epithelial to mesenchymal transition [ 34 ], cancer stem cell phenotype [ 35 ], and regulates the function of receptor tyrosine kinases [ 36 ] and oncogenes [ 33 ].…”

Section: Glucose Metabolism In Cancermentioning

confidence: 99%

Heterogeneity of Glucose Transport in Lung Cancer

Rivera

Scafoglio

2020

Biomolecules

View full text Add to dashboard Cite

Increased glucose uptake is a known hallmark of cancer. Cancer cells need glucose for energy production via glycolysis and the tricarboxylic acid cycle, and also to fuel the pentose phosphate pathway, the serine biosynthetic pathway, lipogenesis, and the hexosamine pathway. For this reason, glucose transport inhibition is an emerging new treatment for different malignancies, including lung cancer. However, studies both in animal models and in humans have shown high levels of heterogeneity in the utilization of glucose and other metabolites in cancer, unveiling a complexity that is difficult to target therapeutically. Here, we present an overview of different levels of heterogeneity in glucose uptake and utilization in lung cancer, with diagnostic and therapeutic implications.

show abstract

“…Aberrations in the glycosylation processes have been reported to occur frequently in tumor cells. Truncation of the O -glycan chains at the cell surface of cancer cells result in the formation of T (Galβ1-3GalNAcα1-O-Ser/Thr, i.e., CD176) and Tn (GalNAcα1-O-Ser/Thr, i.e., CD175) antigens [8,9,10,11,12]. In healthy cells, Tn and T consist of the first and second step in the O -glycosylation biosynthesis pathway, respectively, just before a further elongation giving longer Gal/GalNAc-containing O -glycans.…”

Section: Introductionmentioning

confidence: 99%

Morniga-G, a T/Tn-Specific Lectin, Induces Leukemic Cell Death via Caspase and DR5 Receptor-Dependent Pathways

Poiroux

Barre²,

Simplicien³

et al. 2019

IJMS

View full text Add to dashboard Cite

Morniga-G, the Gal-specific black mulberry (Morus nigra) lectin, displays high affinity for T (CD176) and Tn (CD175) antigens, frequently expressed at the cancer cell surface. The effects of Morniga-G were investigated on a Tn-positive leukemic Jurkat cell line. The lectin, used in a concentration range between 5–20 μg/mL, induced cell death in leukemic Jurkat cells. Microscopic and cytofluorometric analyses indicated that Jurkat cell death was essentially apoptotic, associated with an increase in the ceramide content and a depolarization of the mitochondrial transmembrane potential. This lectin-mediated cell death was inhibited by the pan caspase-inhibitor zVAD. In addition, cleavage of caspases 8, 9, and 3 was observed in Morniga-G-treated Jurkat cells whereas Jurkat cell lines that are deficient in caspase 8–10, caspase 9, or FADD, survived to the lectin-mediated toxicity. Furthermore, in the presence of TRAIL- or DR5-blocking mononoclonal antibodies, Jurkat cells became resistant to Morniga-G, suggesting that the lectin triggers cell death via the TRAIL/DR5 pathway. In silico computer simulations suggest that Morniga-G might facilitate both the DR5 dimerization and the building of TRAIL/DR5 complexes. Finally, upon treatment of Jurkat cells with benzyl-GalNAc, an O-glycosylation inhibitor, a decrease in Tn antigen expression associating with a reduced Morniga-G toxicity, was observed. Taken together, these results suggest that Morniga-G induces the cell death of Tn-positive leukemic cells via concomitant O-glycosylation-, caspase-, and TRAIL/DR5-dependent pathways.

show abstract

O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis

Cited by 54 publications

References 53 publications

The hexosamine biosynthesis pathway is a targetable liability in lung cancers with concurrent KRAS and LKB1 mutations

The hexosamine biosynthesis pathway is a targetable liability in lung cancers with concurrent KRAS and LKB1 mutations

Heterogeneity of Glucose Transport in Lung Cancer

Morniga-G, a T/Tn-Specific Lectin, Induces Leukemic Cell Death via Caspase and DR5 Receptor-Dependent Pathways

Contact Info

Product

Resources

About