ASCT2 is a major contributor to serine uptake in cancer cells
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ABSTRACT:
PROVIDER: PRJNA1122640 | ENA |
REPOSITORIES: ENA
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Project description:The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo, others are auxotrophic and therefore reliant on serine uptake. Importantly, despite several transporters being known to be capable of transporting serine, the transporter(s) that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (SLC1A5) as a major contributor to serine uptake in cancer cells. ASCT2 is well-known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that ERα promotes serine uptake by directly activating SLC1A5 transcription. Together, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target.
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Project description:Obesity, and visceral adiposity in particular, increases the risk of common metabolic diseases, including type 2 diabetes, cardiovascular disease, and several forms of cancer. However, the molecular mechanisms responsible for regional fat storage remain poorly characterized, preventing therapeutic innovation. We here applied a systematic genome-wide screen and translational approach, and discovered a novel role for the adipocyte-expressed neutral amino acid transporter SLC7A10/ASC-1 in the regulation of visceral adiposity. Among 65 genes showing both adipose depot-dependent and fat loss-dependent expression, 27 genes further showed significant correlations with waist-to-hip (WHR) ratio adjusted for BMI. Among these ASC-1 was expressed at the highest level in isolated visceral adipocytes. Further, we found decreased ASC-1 mRNA in visceral, and not subcutaneous adipose tissue, in carriers of the KLF14 type 2 diabetes risk allele compared to the protective allele. By profiling amino acid fluxes during adipocyte differentiation in vitro, we found that ASC-1 inhibition by a selective inhibitor decreased adipocyte uptake particularly of serine in mature adipocytes. Interestingly, radiometric amino acid uptake assays showed ASC-1 dependent uptake of the serine D-enantiomere. Using primary human and murine adipocyte models, we uncovered marked effects of inhibiting ASC-1 on mitochondrial respiratory capacity (within hours) and lipid accumulation (within days). Finally, Asc-1 knockout (KO) zebrafish had increased body weight and adipocyte enlargement upon eight-week overfeeding compared to wild-type (WT) fish. RNA sequencing data from zebrafish adipose tissue showed up-regulation of genes involved in fatty acid and lipid metabolism in the ASC-1 KOs, consistent with the increased lipid accumulation in the inhibitor-treated cell models. Additionally, duox, an enzyme involved in ROS generation, showed higher expression in the KOs compared to the WTs. Importantly, we confirmed increased reactive oxygen species (ROS) generation (within minutes and within hours) when inhibiting ASC-1 in our in vitro cell models. Our study points to increased ROS generation and reduced mitochondrial respiratory capacity as central early mechanisms in development of visceral adiposity, and a role for adipocyte D-serine transport via ASC-1 in these processes. Enhancing ASC-1 expression and/or activity in adipocytes, likely through primary effects on one-carbon metabolism and redox balance, is a promising therapeutic strategy for reducing visceral adiposity and related diseases.
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Project description:Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM isoform, effectively constraining lower glycolysis. Here, we report the discovery of novel PKM activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the non-essential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress. A549 cancer cells were treated with compound-16 for up to 24 hours in the presence and absence of serine in the media.
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Project description:Serine is a non-essential amino acid that is generated by the sequential actions of phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1) and phosphoserine phosphatase (PSPH). Increased serine biosynthesis occurs in several cancers and supports tumor growth. In addition to serine synthesis, exogenous serine is taken up by cells and can also fuel tumor growth. Interestingly, colon cancer cells increase expression of serine biosynthesis enzymes in the absence of exogenous serine, suggesting a compensatory adaptive response to reduced availability of serine. This study explored the relative contributions of exogenous and synthesized serine to colon cancer cell growth, metabolism and response to anti-cancer therapy.
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