(Press-News.org) Oncotarget recently published "Exploiting the metabolic dependencies of the broad amino acid transporter SLC6A14" which reported that Tumor cells typically enhance their metabolic capacity to sustain their higher rate of growth and proliferation.
One way to elevate the nutrient intake into cancer cells is to increase the expression of genes encoding amino acid transporters, which may represent targetable vulnerabilities.
The Oncotarget authors analyze the pattern of transcriptional changes in a panel of breast cancer cell lines upon metabolic stress and found that SLC6A14 expression levels are increased in the absence of methionine.
Methionine deprivation, which can be achieved via modulation of dietary methionine intake in tumor cells, in turn leads to a heightened activation of the AMP-activated kinase in SLC6A14-deficient cells.
While SLC6A14 genetic deficiency does not have a major impact on cell proliferation, combined depletion of AMPK and SLC6A14 leads to an increase in apoptosis upon methionine starvation, suggesting that combined targeting of SLC6A14 and AMPK can be exploited as a therapeutic approach to starve tumor cells.
"Suggesting that combined targeting of SLC6A14 and AMPK can be exploited as a therapeutic approach to starve tumor cells"
Dr. Balca R. Mardin from The BioMed X Institute said, "One of the hallmarks of tumors is their deregulated metabolism."
Since amino acids are used for the synthesis of macromolecules required for sustaining the accelerated growth of tumor cells, blocking the amino acid transporters may present as a viable therapeutic option, leading to amino acid starvation selectively in tumor cells.
Consistent with the idea that the function of the amino acid transporters can be more critical for the maintenance of tumor cells, several amino acid transporters are reported to be overexpressed in a wide spectrum of tumors.
For instance, in breast cancer, the metabolism of non-essential amino acids is found to be altered and the expression of amino acid transporters correlates with tumor growth and progression.
The amino acid transporter SLC6A14 is a highly concentrative symporter which makes use of the sodium and chloride gradient to uptake amino acids.
Although in vitro studies have revealed variable affinities of each substrate, SLC6A14 can transport the highest range of amino acids compared to all the other amino acid transporters.
The Mardin Research Team concluded in their Oncotarget Research Paper that Increased levels of phosphorylated AMPK in SLC6A14 KO cells challenged with amino acid stress prompted us to test whether blocking AMPK activation can be a vulnerability under these conditions.
For this experiment, the authors transfected gRNAs targeting PRKAA1 and PRKAA2, which encode AMPK α1 and AMPK α2 subunits respectively, in our isogenic cell lines.
Consistent with the fact that SLC6A14 KO alone induces a mild activation of AMPK, they observed a moderate decrease in the cell proliferation rate only in the SLC6A14 KO cell line.
This combination seems to be most pronounced upon SLC6A14 KO, in line with their previous results demonstrating the highest increase of AMPK activation in SLC6A14 KO cells.
Altogether, the data indicate that AMPK activation is a metabolic vulnerability in SLC6A14-deficient cells that can be exploited as a therapeutic approach to drive unbalanced metabolism in starved tumor cells.
Sign up for free Altmetric alerts about this article
DOI - https://doi.org/10.18632/oncotarget.27758
Full text - https://www.oncotarget.com/article/27758/text/
Correspondence to - Balca R. Mardin - mardin@bio.mx
Keywords -
SLC6A14,
metabolic stress,
transcriptional regulation,
methionine,
AMPK
About Oncotarget
Oncotarget is a biweekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.
To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:
SoundCloud - https://soundcloud.com/oncotarget
Facebook - https://www.facebook.com/Oncotarget/
Twitter - https://twitter.com/oncotarget
LinkedIn - https://www.linkedin.com/company/oncotarget
Pinterest - https://www.pinterest.com/oncotarget/
Reddit - https://www.reddit.com/user/Oncotarget/
Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls
Oncotarget recently published "Effect of liver fibrosis on survival in patients with intrahepatic cholangiocarcinoma: a SEER population-based study" which reported that the impact of fibrosis on overall and cancer-specific survival 12, 36, and 60 months following diagnosis, was evaluated in the entire cohort and in subgroups stratified according to treatment approach and the American Joint Committee on Cancer tumor stage using a Cox proportional-hazards model.
After adjusting for age, sex, race, year of diagnosis, AJCC stage, and surgical treatment strategy, advanced fibrosis was associated with worse cancer-specific survival across follow-up periods.
Similar effects were observed for overall survival.
Among patients that underwent surgical resection, ...
CHICAGO --- Public attitude toward COVID-19 and its treatments is more "infectious" than the disease itself, according to a new Northwestern Medicine study using Artificial Intelligence (AI) to analyze tweets about the virus. Researchers studied the influence of Twitter on COVID-19 health beliefs as well as the competing influence of scientific evidence versus the speeches of politicians.
The study's key findings:
People's biases are magnified when they read tweets about COVID-19 from other users, and the more times it has been retweeted, the more they tend to believe it and retweet it themselves.
Scientific ...
WINSTON-SALEM, N.C. - March 1, 2021 - There is a growing recognition in health care that social factors such as racial bias, access to care and housing and food insecurity, have a significant impact on people's health. Compounding and amplifying those underlying inequalities are the ongoing disruptions related to the COVID-19 pandemic and social unrest in our country.
Although many health care organizations (National Academy of Medicine, American College of Physicians and the American Academy of Pediatrics) currently recommend that screening for social determinants of health (SDH) be included in clinical care, medical education has lagged ...
What The Study Did: Researchers assessed the recruitment and results reporting of randomized clinical trials (RCTs) to treat or prevent COVID-19 registered within 100 days of the first case reported to the World Health Organization.
Authors: Lars G. Hemkens, M.D., M.P.H., of the University Hospital Basel in Basel, Switzerland, is the corresponding author.
To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/
(doi:10.1001/jamanetworkopen.2021.0330)
Editor's Note: The article includes conflict of interest and funding/support disclosures. Please ...
Researchers from the Institute of Process Engineering (IPE) of the Chinese Academy of Sciences and Nanjing Normal University recently reported a strategy for boosting the electrocatalytic performance of palladium (Pd) in ethanol oxidation reaction, the key anodic reaction of direct ethanol fuel cells (DEFCs), offering a rational concept for finely engineering the surface of electrocatalysts used in high-efficiency energy conversion devices and beyond.
The study was published in Cell Reports Physical Science on Mar. 1.
DEFCs, with ethanol as fuel, have the advantage of high energy density, low toxicity and easy operation. However, the lack of active and robust electrocatalysts ...
Rising temperatures could reduce the efficiency of food chains and threaten the survival of larger animals, new research shows.
Scientists measured the transfer of energy from single-celled algae (phytoplankton) to small animals that eat them (zooplankton).
The study - by the University of Exeter and Queen Mary University of London, and published in the journal Nature - found that 4°C of warming reduced energy transfer in the plankton food webs by up to 56%.
Warmer conditions increase the metabolic cost of growth, leading to less efficient energy flow through the ...
Researchers in the Muir Lab at Princeton University's Department of Chemistry have completed the first comprehensive analysis of cancer-associated histone mutations in the human genome, featuring both biochemical and cellular characterizations of these substrates. Their study reports that histone mutations that perturb nucleosome remodeling may contribute to the development or progression of a wide range of human cancers.
Within the human genome, DNA is wrapped around disc-shaped structures made up of eight histone proteins, each forming nucleosomes. Repeating nucleosome units comprise chromatin, a storehouse of genetic information that is both structured and dynamic. Broadly, the Muir Lab seeks to understand how chromatin controls genetic processes in the cell and how disruption ...
MADISON, Wis. -- Grafting neurons grown from monkeys' own cells into their brains relieved the debilitating movement and depression symptoms associated with Parkinson's disease, researchers at the University of Wisconsin-Madison reported today.
In a study published in the journal Nature Medicine, the UW team describes its success with neurons made from induced pluripotent stem cells from the monkeys' own bodies. This approach avoided complications with the primates' immune systems and takes an important step toward a treatment for millions of human Parkinson's patients.
"This result in primates is ...
Extreme rainfall associated with climate change is causing harm to babies in some of the most forgotten places on the planet setting in motion a chain of disadvantage down the generations, according to new research in Nature Sustainability.
Researchers from Lancaster University and the FIOCRUZ health research institute in Brazil found babies born to mothers exposed to extreme rainfall shocks, were smaller due to restricted foetal growth and premature birth.
Low birth-weight has life-long consequences for health and development and researchers say their findings are evidence of climate extremes causing intergenerational disadvantage, especially for socially-marginalized Amazonians in forgotten places.
Climate extremes can affect the health of mothers and their unborn babies in ...
BINGHAMTON, NY -- Neandertals -- the closest ancestor to modern humans -- possessed the ability to perceive and produce human speech, according to a new study published by an international multidisciplinary team of researchers including Binghamton University anthropology professor Rolf Quam and graduate student Alex Velez.
"This is one of the most important studies I have been involved in during my career", says Quam. "The results are solid and clearly show the Neandertals had the capacity to perceive and produce human speech. This is one of the very few current, ongoing research lines relying on fossil evidence to study the evolution of language, a notoriously ...
