Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma

Rathore, Richa; Caldwell, Kevin K.; Schutt, Charles R.; Brashears, Caitlyn B.; Prudner, Bethany C.; Ehrhardt, William R.; Leung, Cheuk Hong; Lin, Heather; Daw, Najat C.; Beird, Hannah C.; Giles, Abigail; Wang, Wei Lien; Lazar, Alexander J.; Chrisinger, John S.A.; Livingston, J. Andrew; Tine, Brian Andrew Van

doi:10.1016/j.celrep.2020.108678

Cited by 38 publications

(47 citation statements)

References 67 publications

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“…SAMTOR and GATOR1 interactions are dependent on KICSTOR (see below). When SAMTOR is bound to SAM, it dissociates from GATOR1-KICSTOR, thus inhibiting GATOR1 and promoting mTORC1 activation [101]. On the other hand, methionine starvation promotes interaction between SAMTOR and the GATOR1-KICKSTOR complex, but weakened the interaction between GATOR1 and GATOR2, thus leading to mTORC1 suppression [100].…”

Section: Gator1 Interaction With Sam Sensor Samtormentioning

confidence: 99%

SEA and GATOR 10 Years Later

Loissell-Baltazar

Dokudovskaya

2021

Cells

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The SEA complex was described for the first time in yeast Saccharomyces cerevisiae ten years ago, and its human homologue GATOR complex two years later. During the past decade, many advances on the SEA/GATOR biology in different organisms have been made that allowed its role as an essential upstream regulator of the mTORC1 pathway to be defined. In this review, we describe these advances in relation to the identification of multiple functions of the SEA/GATOR complex in nutrient response and beyond and highlight the consequence of GATOR mutations in cancer and neurodegenerative diseases.

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Section: Gator1 Interaction With Sam Sensor Samtormentioning

confidence: 99%

SEA and GATOR 10 Years Later

Loissell-Baltazar

Dokudovskaya

2021

Cells

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“…Osteosarcoma is the prevalent malignant bone cancer principally befalling throughout adolescence and childhood (Du et al, 2021;Gioti et al, 2021). Osteosarcoma emphasizes the profoundly malignant phenotypes, and 75% of osteosarcoma cells migrate nearby tissues (Li et al, 2021;Rathore et al, 2021). Although the overall 5-years survival incidence of osteosarcoma patients has improved by applying surgery and chemotherapy over the past 30 years, prognosis continues unsatisfactory due to drug resistance and metastasis (Wen et al, 2020;Tornin et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Graphene Oxide Nanoparticle–Loaded Ginsenoside Rg3 Improves Photodynamic Therapy in Inhibiting Malignant Progression and Stemness of Osteosarcoma

Wang

Liu

et al. 2021

Front. Mol. Biosci.

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Osteosarcoma serves as a prevalent bone cancer with a high metastasis and common drug resistance, resulting in poor prognosis and high mortality. Photodynamic therapy (PDT) is a patient-specific and non-invasive tumor therapy. Nanoparticles, like graphene oxide have been widely used in drug delivery and PDT. Ginsenoside Rg3 is a principal ginseng component and has presented significant anti-cancer activities. Here, we constructed the nanoparticles using GO linked with photosensitizer (PS) indocyanine green (ICG), folic acid, and polyethylene glycol (PEG), and loaded with Rg3 (PEG–GO–FA/ICG–Rg3). We aimed to explore the effect of PEG–GO–FA/ICG–Rg3 combined with PDT for the treatment of osteosarcoma. Significantly, we found that Rg3 repressed proliferation, invasion, and migration, and enhanced apoptosis and autophagy of osteosarcoma cells, while the PEG–GO–FA/ICG–Rg3 presented a higher activity, in which NIR laser co-treatment could remarkably increase the effect of PEG–GO–FA/ICG–Rg3. Meanwhile, stemness of osteosarcoma cell–derived cancer stem cells was inhibited by Rg3 and PEG–GO–FA/ICG–Rg3, and the combination of PEG–GO–FA/ICG–Rg3 with NIR laser further significantly attenuated this phenotype in the system. Moreover, NIR laser notably improved the inhibitor effect of PEG–GO–FA/ICG–Rg3 on the tumor growth of osteosarcoma cells in vivo. Consequently, we concluded that PEG–GO–FA/ICG–Rg3 improved PDT in inhibiting malignant progression and stemness of osteosarcoma cell. Our finding provides a promising and practical therapeutic strategy for the combined treatment of osteosarcoma.

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“…A previously published study illustrated the importance of metabolism in OS as metastatic OS cells were found to be highly metabolically active, and therefore targeting metabolism in OS can be a potential novel therapy [6]. Furthermore, it was shown that both the inhibition of mTOR-a key regulator of metabolism, and the inhibition of 3-phosphoglycerate dehydrogenase (PHGDH)-the rate-limiting enzyme of serine biosynthesis, attenuated cell proliferation in OS cells and can therefore serve as a novel therapeutic target [7][8][9]. The NAD+ synthesis pathway is a metabolic pathway often upregulated in tumors as cancer cells need to maintain a high level of NAD+ required for cell survival processes [10,11].…”

Section: Introductionmentioning

confidence: 99%

Targeting the NAD Salvage Synthesis Pathway as a Novel Therapeutic Strategy for Osteosarcomas with Low NAPRT Expression

Franceschini

Oosting

Tamsma

et al. 2021

IJMS

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For osteosarcoma (OS), the most common primary malignant bone tumor, overall survival has hardly improved over the last four decades. Especially for metastatic OS, novel therapeutic targets are urgently needed. A hallmark of cancer is aberrant metabolism, which justifies targeting metabolic pathways as a promising therapeutic strategy. One of these metabolic pathways, the NAD+ synthesis pathway, can be considered as a potential target for OS treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the classical salvage pathway for NAD+ synthesis, and NAMPT is overexpressed in OS. In this study, five OS cell lines were treated with the NAMPT inhibitor FK866, which was shown to decrease nuclei count in a 2D in vitro model without inducing caspase-driven apoptosis. The reduction in cell viability by FK866 was confirmed in a 3D model of OS cell lines (n = 3). Interestingly, only OS cells with low nicotinic acid phosphoribosyltransferase domain containing 1 (NAPRT1) RNA expression were sensitive to NAMPT inhibition. Using a publicly available (Therapeutically Applicable Research to Generate Effective Treatments (TARGET)) and a previously published dataset, it was shown that in OS cell lines and primary tumors, low NAPRT1 RNA expression correlated with NAPRT1 methylation around the transcription start site. These results suggest that targeting NAMPT in osteosarcoma could be considered as a novel therapeutic strategy, where low NAPRT expression can serve as a biomarker for the selection of eligible patients.

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Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma

Cited by 38 publications

References 67 publications

SEA and GATOR 10 Years Later

SEA and GATOR 10 Years Later

Graphene Oxide Nanoparticle–Loaded Ginsenoside Rg3 Improves Photodynamic Therapy in Inhibiting Malignant Progression and Stemness of Osteosarcoma

Targeting the NAD Salvage Synthesis Pathway as a Novel Therapeutic Strategy for Osteosarcomas with Low NAPRT Expression

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