The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer

Najumudeen, Arafath K.; Ceteci, Fatih; Fey, Sigrid K.; Hamm, Grégory; Steven, Rory T.; Hall, Holly; Nikula, Chelsea; Dexter, Alex; Murta, Teresa; Race, Alan; Sumpton, David; Vlahov, Nikola; Knight, John R. P.; Jackstadt, René; Leach, Joshua D.G.; Ridgway, Rachel A.; Johnson, Emma; Nixon, Colin; Hedley, Ann; Gilroy, Kathryn; Clark, William; Malla, Sudhir B.; Dunne, Philip D.; Blanco, Giovanny Rodriguez; Critchlow, Susan E.; Mrowinska, Agata; Malviya, Gaurav; Solovyev, D.; Brown, Gavin; Lewis, David Y.; Mackay, Gillian; Strathdee, Douglas; Tardito, Saverio; Gottlieb, Eyal; Takáts, Zoltán; Barry, Simon T.; Goodwin, Richard J. A.; Bunch, Josephine; Bushell, Martin; Campbell, Andrew D.; Sansom, Owen J.

doi:10.1038/s41588-020-00753-3

Cited by 168 publications

(121 citation statements)

References 56 publications

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“…Tumors driven by c-Myc or KRAS are particularly dependent on exogenous Gln [18,19]. This not only validates Gln as a therapeutic target, but can also be exploited for diagnostic imaging where tumors are detected in PET scans as a result of accumulation of radiolabeled Gln [5].…”

Section: Glutaminementioning

confidence: 66%

Amino Acid Depletion Therapies: Starving Cancer Cells to Death

Butler

Meer

Leeuwen

2021

Trends in Endocrinology & Metabolism

169

124

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Targeting tumor cell metabolism is an attractive form of therapy, as it may enhance treatment response in therapy resistant cancers as well as mitigate treatment-related toxicities by reducing the need for genotoxic agents. To meet their increased demand for biomass accumulation and energy production and to maintain redox homeostasis, tumor cells undergo profound changes in their metabolism. In addition to the diversion of glucose metabolism, this is achieved by upregulation of amino acid metabolism. Interfering with amino acid availability can be selectively lethal to tumor cells and has proven to be a cancer specific Achilles' heel. Here we review the biology behind such cancer specific amino acid dependencies and discuss how these vulnerabilities can be exploited to improve cancer therapies.

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Section: Glutaminementioning

confidence: 66%

Amino Acid Depletion Therapies: Starving Cancer Cells to Death

Butler

Meer

Leeuwen

2021

Trends in Endocrinology & Metabolism

169

124

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“…A marked positive correlation between higher expression of LAT1 in renal cancers and frequent metastasis/poor prognosis may explain the significant effects of mTOR inhibitors on renal cancers [ 45 , 46 ]. In this context, LAT1 is required for efficient growth of KRAS-mutant colorectal cancer, and rapamycin reduces LAT1-deficient cell proliferation and tumor formation [ 47 ], suggesting LAT1 as an attractive therapeutic target for various cancers.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic transformation of NIH/3T3 cells by the overexpression of L-type amino acid transporter 1, a promising anti-cancer target

et al. 2021

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L-type amino acid transporter 1 (LAT1)/SLC7A5 is the first identified CD98 light chain disulfide linked to the CD98 heavy chain (CD98hc/SLC3A2). LAT1 transports large neutral amino acids, including leucine, which activates mTOR, and is highly expressed in human cancers. We investigated the oncogenicity of human LAT1 introduced to NIH/3T3 cells by retrovirus infection. NIH/3T3 cell lines stably expressing human native (164C) or mutant (164S) LAT1 (naLAT1/3T3 or muLAT1/3T3, respectively) were established. We confirmed that endogenous mouse CD98hc forms a disulfide bond with exogenous human LAT1 in naLAT1/3T3, but not in muLAT1/3T3. Endogenous mouse CD98hc mRNA increased in both naNIH/3T3 and muLAT1/3T3, and a similar amount of exogenous human LAT1 protein was detected in both cell lines. Furthermore, naLAT1/3T3 and muLAT1/3T3 cell lines were evaluated for cell growth-related phenotypes (phosphorylation of ERK, cell-cycle progression) and cell malignancy-related phenotypes (anchorage-independent cell growth, tumor formation in nude mice). naLAT1/3T3 had stronger growth-and malignancy-related phenotypes than NIH/3T3 and muLAT1/3T3, suggesting the oncogenicity of native LAT1 through its interaction with CD98hc. Anti-LAT1 monoclonal antibodies significantly inhibited in vitro cell proliferation and in vivo tumor growth of naLAT1/3T3 cells in nude mice, demonstrating LAT1 to be a promising anti-cancer target. Oncotarget 12 www.oncotarget.complotted against the ΔMFI, and the dissociation constant: K D (nmol/L) and avidity constant: K A (M -1 ) were determined from the slope of linear regression. Statistical analysisAll data are shown as the average ± SEM. The criteria for significance were * P < 0.05, ** P < 0.01, and *** P < 0.001. The data were analyzed by one-or two-way analysis of variance (ANOVA) followed by Tukey's post hoc multiple comparison test (Figures 1-5).

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“…Thus, plasma membrane transport of BCAA and/or glutamine may not be limiting or is highly dependent on the cellular context, and minimal transport capacity may be sufficient to satisfy the biosynthetic and catabolic demands for these amino acids. In contrast, LAT1 was significantly upregulated in an Apc fl/fl ; LSL-Kras G12D/+ ; Villin CreER mouse model of colorectal cancer, and targeted deletion of Slc7a5 resulted in delayed tumorigenesis and improved survival [169]. Furthermore, JPH203, a small molecule inhibitor of LAT1, has shown significant pre-clinical efficacy in colorectal cancer and T-cell lymphoblastic lymphoma/leukemia and was well-tolerated in a Phase I study in patients with advanced solid tumors [170][171][172].…”

Section: Branched-chain Amino Acidsmentioning

confidence: 94%

Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism

2021

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Mitochondria are central organelles that coordinate a vast array of metabolic and biologic functions important for cellular health. Amino acids are intricately linked to the bioenergetic, biosynthetic, and homeostatic function of the mitochondrion and require specific transporters to facilitate their import, export, and exchange across the inner mitochondrial membrane. Here we review key cellular metabolic outputs of eukaryotic mitochondrial amino acid metabolism and discuss both known and unknown transporters involved. Furthermore, we discuss how utilization of compartmentalized amino acid metabolism functions in disease and physiological contexts. We examine how improved methods to study mitochondrial metabolism, define organelle metabolite composition, and visualize cellular gradients allow for a more comprehensive understanding of how transporters facilitate compartmentalized metabolism.

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The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer

Cited by 168 publications

References 56 publications

Amino Acid Depletion Therapies: Starving Cancer Cells to Death

Amino Acid Depletion Therapies: Starving Cancer Cells to Death

Oncogenic transformation of NIH/3T3 cells by the overexpression of L-type amino acid transporter 1, a promising anti-cancer target

Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism

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