CD98 signals controlling tumorigenesis

Ip, Hugh; Sethi, Tariq

doi:10.1016/j.biocel.2016.11.005

Cited by 21 publications

(27 citation statements)

References 22 publications

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“…CD98 promotes LAT1 protein stability and mediates the translocation of LAT1 to the cell membrane [2]. Deciphering the role of CD98 in cancer is complicated because its effects could be due to enhancing amino acid signaling or integrin signaling [21]. Cormerais et al (2016) approached this question by comparing LAT1 effects with CD98 effects in LS1747 colon cancer cells [3].…”

Section: Interactions Between Cd98 and Lat1mentioning

confidence: 99%

The Regulation and Function of the L-Type Amino Acid Transporter 1 (LAT1) in Cancer

Salisbury

Arthur

2018

IJMS

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The progression of cancer is associated with increases in amino acid uptake by cancer cells. Upon their entry into cells through specific transporters, exogenous amino acids are used to synthesize proteins, nucleic acids and lipids and to generate ATP. The essential amino acid leucine is also important for maintaining cancer-associated signaling pathways. By upregulating amino acid transporters, cancer cells gain greater access to exogenous amino acids to support chronic proliferation, maintain metabolic pathways, and to enhance certain signal transduction pathways. Suppressing cancer growth by targeting amino acid transporters will require an in-depth understanding of how cancer cells acquire amino acids, in particular, the transporters involved and which cancer pathways are most sensitive to amino acid deprivation. L-Type Amino Acid Transporter 1 (LAT1) mediates the uptake of essential amino acids and its expression is upregulated during the progression of several cancers. We will review the upstream regulators of LAT1 and the downstream effects caused by the overexpression of LAT1 in cancer cells.

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Section: Interactions Between Cd98 and Lat1mentioning

confidence: 99%

The Regulation and Function of the L-Type Amino Acid Transporter 1 (LAT1) in Cancer

Salisbury

Arthur

2018

IJMS

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“…2J). These include upregulation of the master metabolic transcription factor c-myc, as well as several other metabolic enzymes and solute transporters (26)(27)(28). These data cumulatively suggest that DTA-1 treatment increases global cellular metabolism, even when proliferation is not enhanced.…”

Section: Dta-1 Enhances Cd8 þ T-cell Activation Despite Optimal Anti-mentioning

confidence: 89%

GITR Agonism Enhances Cellular Metabolism to Support CD8+ T-cell Proliferation and Effector Cytokine Production in a Mouse Tumor Model

Sabharwal¹,

Rosen²,

Grein³

et al. 2018

Cancer Immunology Research

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GITR is a costimulatory receptor currently undergoing phase I clinical trials. Efficacy of anti-GITR therapy in syngeneic mouse models requires regulatory T-cell depletion and CD8 T-cell costimulation. It is increasingly appreciated that immune cell proliferation and function are dependent on cellular metabolism. Enhancement of diverse metabolic pathways leads to different immune cell fates. Little is known about the metabolic effects of GITR agonism; thus, we investigated whether costimulation via GITR altered CD8 T-cell metabolism. We found activated, GITR-treated CD8 T cells upregulated nutrient uptake, lipid stores, glycolysis, and oxygen consumption rate (OCR) Using MEK, PI3Kδ, and metabolic inhibitors, we show increased metabolism is required, but not sufficient, for GITR antibody (DTA-1)-induced cellular proliferation and IFNγ production. In an model of PD-L1-induced CD8 T-cell suppression, GITR agonism alone rescued cellular metabolism and proliferation, but not IFNγ production; however, DTA-1 in combination with anti-PD-1 treatment increased IFNγ production. In the MC38 mouse tumor model, GITR agonism significantly increased OCR and IFNγ and granzyme gene expression in both tumor and draining lymph node (DLN) CD8 T cells , as well as basal glycolysis in DLN and spare glycolytic capacity in tumor CD8 T cells. DLN in GITR-treated mice showed significant upregulation of proliferative gene expression compared with controls. These data show that GITR agonism increases metabolism to support CD8 T-cell proliferation and effector function , and that understanding the mechanism of action of agonistic GITR antibodies is crucial to devising effective combination therapies..

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“…SLC3A2 forms a complex with LAT1 for amino acid transport activity 4 , 5 , 7 . We demonstrated that LAT1 expression level was gradually increased during HCV infection and SLC3A2/LAT1 complex level was also elevated in Jc1-infected cells.…”

Section: Discussionmentioning

confidence: 99%

“…Solute carrier family 3 member 2 (SLC3A2), a gene encoding for a subunit of heterodimeric amino acid transporter, belongs to CD98 family and regulates intracellular amino acid levels. The CD98 family is composed of widely expressed cell surface disulfide-linked 125-kDa heterodimeric type II membrane glycoproteins containing an 80-kDa glycosylated heavy chain (SLC3A2) and a 45-kDa non-glycosylated light chain (LAT1) 4 , 5 . SLC3A2 consists of three domains, including the extracellular domain, the transmembrane domain, and the cytoplasmic domain 4 .…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C Virus Modulates Solute carrier family 3 member 2 for Viral Propagation

Nguyen

Lim

Nguyen

et al. 2018

Sci Rep

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Hepatitis C virus (HCV) exploits an extensive network of host proteins to maintain chronic infection. Using RNA-Seq technology, we identified 30 host genes that were differentially expressed in cell culture grown HCV (HCVcc)-infected cells. Of these candidate genes, we selected solute carrier family 3 member 2 (SLC3A2) for further investigation. SLC3A2, also known as CD98hc, is a member of the solute carrier family and encodes a subunit of heterodimeric amino acid transporter. SLC3A2 and LAT1 constitute a heterodimeric transmembrane protein complex that catalyzes amino acid transport. In this study, we showed that HCV upregulated both mRNA and protein expression levels of SLC3A2 and this upregulation occurred through NS3/4A-mediated oxidative stress. HCV also elevated SLC3A2/LAT1 complex level and thus mammalian target of rapamycin complex 1 (mTORC1) signaling was activated. We further showed that L-leucine transport level was significantly increased in Jc1-infected cells as compared with mock-infected cells. Using RNA interference technology, we demonstrated that SLC3A2 was specifically required for the entry step but not for other stages of the HCV life cycle. These data suggest that SLC3A2 plays an important role in regulating HCV entry. Collectively, HCV exploits SLC3A2 for viral propagation and upregulation of SLC3A2 may contribute to HCV-mediated pathogenesis.

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CD98 signals controlling tumorigenesis

Cited by 21 publications

References 22 publications

The Regulation and Function of the L-Type Amino Acid Transporter 1 (LAT1) in Cancer

The Regulation and Function of the L-Type Amino Acid Transporter 1 (LAT1) in Cancer

GITR Agonism Enhances Cellular Metabolism to Support CD8+ T-cell Proliferation and Effector Cytokine Production in a Mouse Tumor Model

Hepatitis C Virus Modulates Solute carrier family 3 member 2 for Viral Propagation

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