Effects of targeting SLC1A5 on inhibiting gastric cancer growth and tumor development <i>in vitro</i> and <i>in vivo</i>

Lü, Jian; Chen, Min; Tao, Zhenhua; Gao, Sumeng; Yang, Li; Cao, Yu; Liu, Chun; Zou, Xiaoping

doi:10.18632/oncotarget.19479

Cited by 43 publications

(33 citation statements)

References 27 publications

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“…Directly inhibiting transport of these nutrients may be a more efficacious approach to targeting the metabolic demands of PDAC and other cancers. Several reports have demonstrated that targeting glutamine transport through inhibition of SLC1A5/ ASCT2 has profound impacts on tumor growth in gastric and breast cancers (49,50). In addition, targeting other amino acid transporters, including SLC6A14 and SLC7A11/xCT, has also been reported to have significant impacts on tumor growth in PDAC (51,52).…”

Section: Discussionmentioning

confidence: 99%

Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSC). Previous studies have demonstrated that stromal supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine crosstalk between PSCs and PDAC is orchestrated by the utilization of specifi c transporters. PSCs utilize SLC1A4 and other transporters to rapidly exchange and maintain environmental alanine concentrations. Moreover, PDAC cells upregulate SLC38A2 to supply their increased alanine demand. Cells lacking SLC38A2 fail to concentrate intracellular alanine and undergo a profound metabolic crisis resulting in markedly impaired tumor growth. Our results demonstrate that stromal-cancer metabolic niches can form through differential transporter expression, creating unique therapeutic opportunities to target metabolic demands of cancer. SIGnIFICAnCE: This work identifi es critical neutral amino acid transporters involved in channeling alanine between pancreatic stellate and PDAC cells. Targeting PDAC-specifi c alanine uptake results in a metabolic crisis impairing metabolism, proliferation, and tumor growth. PDAC cells specifi cally activate and require SLC38A2 to fuel their alanine demands that may be exploited therapeutically.

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Section: Discussionmentioning

confidence: 99%

Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer

et al. 2020

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“…Slc1A5 is a major transporter of glutamine in most cells. Knockdown of ASCT2 diminishes mTORC1 activity and tumor growth [124][125][126][127][128]. Although the absence of Slc1A5 did not significantly diminish intracellular Gln or Glu levels, it disrupted influx of leucine and diminished levels of other amino acids crucial for redox homeostasis [128].…”

Section: Glutamine Metabolismmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

165

128

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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“…There are few published studies reporting the association between ASCT2 and invasion and metastasis and the underlying mechanism remains elusive. Nevertheless, a higher expression of SLC1A5 in gastric cancer tissues has been correlated with clinicopathological features such as local invasion and lymph node metastasis [ 33 ]. Furthermore, SLC1A5 downregulation in vitro resulted in significant inhibition of gastric cells invasion and migration [ 33 ].…”

Section: Asct2 and Lat1: Their Contribution To The Hallmarks Of Camentioning

confidence: 99%

“…Although with fewer published studies, ASCT2 has been identified as a prognostic factor in hepatocellular [ 34 ], lung [ 35 ], colorectal [ 151 ], gastric [ 33 ], renal [ 28 ], ovarian [ 36 , 152 ], breast [ 153 ], tongue [ 140 ] and pancreatic cancer [ 76 ]. Furthermore, genetic variants in the SLC1A5 gene have also been implicated in hepatocellular carcinoma prognosis, with stage I patients carrying the rs2070246 TT genotype showing higher overall survival (OS) than carriers of CC genotype [ 154 ].…”

Section: Asct2 and Lat1: Their Clinical Significance In Cancermentioning

confidence: 99%

ASCT2 and LAT1 Contribution to the Hallmarks of Cancer: From a Molecular Perspective to Clinical Translation

Lopes

Pereira

Medeiros

2021

Cancers

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The role of the amino acid transporters ASCT2 and LAT1 in cancer has been explored throughout the years. In this review, we report their impact on the hallmarks of cancer, as well as their clinical significance. Overall, both proteins have been associated with cell death resistance through dysregulation of caspases and sustainment of proliferative signaling through mTOR activation. Furthermore, ASCT2 appears to play an important role in cellular energetics regulation, whereas LAT1 expression is associated with angiogenesis and invasion and metastasis activation. The molecular impact of these proteins on the hallmarks of cancer translates into various clinical applications and both transporters have been identified as prognostic factors in many types of cancer. Concerning their role as therapeutic targets, efforts have been undertaken to synthesize competitive or irreversible ASCT2 and LAT1 inhibitors. However, JHP203, a selective inhibitor of the latter, is, to the best of our knowledge, the only compound included in a Phase 1 clinical trial. In conclusion, considering the usefulness of ASCT2 and LAT1 in a variety of cancer-related pathways and cancer therapy/diagnosis, the development and testing of novel inhibitors for these transporters that could be evaluated in clinical trials represents a promising approach to cancer prognosis improvement.

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Effects of targeting SLC1A5 on inhibiting gastric cancer growth and tumor development in vitro and in vivo

Cited by 43 publications

References 27 publications

Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer

Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

ASCT2 and LAT1 Contribution to the Hallmarks of Cancer: From a Molecular Perspective to Clinical Translation

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