SLC7A5 Functions as a Downstream Target Modulated by CRKL in Metastasis Process of Gastric Cancer SGC-7901 Cells

Wang, Junqing; Fei, Xiaochun; Wu, Wenjun; Chen, Xuehua; Zhu, Zhenggang; Zhou, Yunyun

doi:10.1371/journal.pone.0166147

Cited by 14 publications

(13 citation statements)

References 28 publications

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“…3A). Indeed, previous immunohistochemistry (IHC) studies found that both SLC1A5 and SLC7A5 were up-regulated in colon cancer cells (Huang et al 2014;Wang et al 2016;Toda et al 2017).…”

Section: Myc Promotes the Expression Of Trp Transporters And Enzymes mentioning

confidence: 99%

MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer

et al. 2019

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Tumors display increased uptake and processing of nutrients to fulfill the demands of rapidly proliferating cancer cells. Seminal studies have shown that the proto-oncogene MYC promotes metabolic reprogramming by altering glutamine uptake and metabolism in cancer cells. How MYC regulates the metabolism of other amino acids in cancer is not fully understood. Using high-performance liquid chromatography (HPLC)-tandem mass spectrometry (LC-MS/MS), we found that MYC increased intracellular levels of tryptophan and tryptophan metabolites in the kynurenine pathway. MYC induced the expression of the tryptophan transporters SLC7A5 and SLC1A5 and the enzyme arylformamidase (AFMID), involved in the conversion of tryptophan into kynurenine. SLC7A5, SLC1A5, and AFMID were elevated in colon cancer cells and tissues, and kynurenine was significantly greater in tumor samples than in the respective adjacent normal tissue from patients with colon cancer. Compared with normal human colonic epithelial cells, colon cancer cells were more sensitive to the depletion of tryptophan. Blocking enzymes in the kynurenine pathway caused preferential death of established colon cancer cells and transformed colonic organoids. We found that only kynurenine and no other tryptophan metabolite promotes the nuclear translocation of the transcription factor aryl hydrocarbon receptor (AHR). Blocking the interaction between AHR and kynurenine with CH223191 reduced the proliferation of colon cancer cells. Therefore, we propose that limiting cellular kynurenine or its downstream targets could present a new strategy to reduce the proliferation of MYC-dependent cancer cells.

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“…3A). Indeed, previous immunohistochemistry (IHC) studies found that both SLC1A5 and SLC7A5 were up-regulated in colon cancer cells (Huang et al 2014;Wang et al 2016;Toda et al 2017).…”

Section: Myc Promotes the Expression Of Trp Transporters And Enzymes mentioning

confidence: 99%

MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer

et al. 2019

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“…GSE1 is positively associated with many clinicopathological features, namely lymph node metastasis, clinical stage, depth of invasion and histological grade and LAT1 appears to mediate its functions and to be positively regulated by GSE1 [ 75 ]. Wang et al [ 47 ] identified LAT1 as a downstream target of the CRK-like (CRKL) protein, a promoter of gastric cancer. Depletion of CRKL in a gastric cancer cell line resulted in impairment of SLC7A5 expression and suppression of cell motility [ 47 ].…”

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

confidence: 99%

“…Wang et al [ 47 ] identified LAT1 as a downstream target of the CRK-like (CRKL) protein, a promoter of gastric cancer. Depletion of CRKL in a gastric cancer cell line resulted in impairment of SLC7A5 expression and suppression of cell motility [ 47 ].…”

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

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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“…LAT1 and LAT2 require a complex formation with 4F2hc (SLC3A2), also known as CD98, for their functional expression 15 . LAT1 and 4F2hc have been reported to be up‐regulated and play an important role in cancer progression in various tumors such as head and neck squamous cell carcinoma,prostate, breast, colon, gastric, and bladder cancers,cholangiocarcinoma,and endometrioid endometrial carcinoma 19‐25 . The up‐regulation of the LAT1‐4F2hc complex supports cancer progression by enhancing the ability to import leucine into the cells, hence triggering the mechanistic target of rapamycin (mTOR) signaling pathway, which is important in cell growth and proliferation 26 .…”

Section: Introductionmentioning

confidence: 99%

Expression and roles of system L amino acid transporters in human embryonal carcinoma cells

et al. 2020

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Background Testicular germ cell tumors (TGCTs) are the most common malignant cancer in young men. Although TGCTs are generally responsive to platinum‐based chemotherapy particularly cisplatin, acquired resistance in patients with metastasis still occurs resulting in poor prognosis. Specifically, differentiation of embryonal carcinoma (EC) cells, the stem cells of TGCTs, can lead to the reduction of cisplatin responsiveness. Therefore, novel therapeutic strategies for TGCTs are needed. System L amino acid transporters have been reported to be up‐regulated and to play an important role in tumorigenesis. However, expression and role of system L amino acid transporters in TGCTs remain elusive. Materials and methods Expression of system L amino acid transporters was analyzed in TGCT samples from The Cancer Genome Atlas (TCGA). Expression of LAT1, LAT2, and 4F2hc was examined in human embryonal carcinoma cell line NTERA2. Roles of system L amino acid transporters on NTERA2 cell survival, cell proliferation, pluripotency, and cisplatin sensitivity were evaluated. Results Based upon TCGA datasets, we found that two isoforms of system L (LAT1 and LAT2) and their chaperone protein 4F2hc are highly expressed in EC samples compared with other groups. Treatment with the system L inhibitor BCH significantly suppressed leucine uptake into the pluripotent EC cell line NTERA2. The malignant phenotypes including cell viability, cell proliferation, and clonal ability were decreased following BCH treatment. Nonetheless, system L inhibition did not alter expression of stemness genes in NTERA2 cells. After NTERA2 differentiation, expressions of LAT1 and LAT2 were decreased. Finally, co‐administration of BCH enhanced cisplatin sensitivity in both undifferentiated and differentiated cells. These effects were associated with the reduction in p70S6K phosphorylation. Conclusion Taken together, these results shed light on the roles of system L amino acid transporters in TGCTs. Therefore, system L amino acid transporters could provide novel therapeutic targets for treatment against TGCTs.

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SLC7A5 Functions as a Downstream Target Modulated by CRKL in Metastasis Process of Gastric Cancer SGC-7901 Cells

Cited by 14 publications

References 28 publications

MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer

MYC promotes tryptophan uptake and metabolism by the kynurenine pathway in colon cancer

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

Expression and roles of system L amino acid transporters in human embryonal carcinoma cells

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