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XCT (SLC7A11) expression confers intrinsic resistance to physical plasma treatment in tumor cells.

ABSTRACT: Cold physical plasma is a partially ionized gas investigated as a new anticancer tool in selectively targeting cancer cells in monotherapy or in combination with therapeutic agents. Here, we investigated the intrinsic resistance mechanisms of tumor cells towards physical plasma treatment. When analyzing the dose-response relationship to cold plasma-derived oxidants in 11 human cancer cell lines, we identified four 'resistant' and seven 'sensitive' cell lines. We observed stable intracellular glutathione levels following plasma treatment only in the 'resistant' cell lines indicative of altered antioxidant mechanisms. Assessment of proteins involved in GSH metabolism revealed cystine-glutamate antiporter xCT (SLC7A11) to be significantly more abundant in the 'resistant' cell lines as compared to 'sensitive' cell lines. This decisive role of xCT was confirmed by pharmacological and genetic inhibition, followed by cold physical plasma treatment. Finally, microscopy analysis of ex vivo plasma-treated human melanoma punch biopsies suggested a correlation between apoptosis and basal xCT protein abundance. Taken together, our results demonstrate that xCT holds the potential as a biomarker predicting the sensitivity of tumor cells towards plasma treatment.

SUBMITTER: Bekeschus S

PROVIDER: S-EPMC6957833 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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xCT (SLC7A11) expression confers intrinsic resistance to physical plasma treatment in tumor cells.

Bekeschus Sander S Eisenmann Sebastian S Sagwal Sanjeev Kumar SK Bodnar Yana Y Moritz Juliane J Poschkamp Broder B Stoffels Ingo I Emmert Steffen S Madesh Muniswamy M Weltmann Klaus-Dieter KD von Woedtke Thomas T Gandhirajan Rajesh Kumar RK

Redox biology 20200103

Cold physical plasma is a partially ionized gas investigated as a new anticancer tool in selectively targeting cancer cells in monotherapy or in combination with therapeutic agents. Here, we investigated the intrinsic resistance mechanisms of tumor cells towards physical plasma treatment. When analyzing the dose-response relationship to cold plasma-derived oxidants in 11 human cancer cell lines, we identified four 'resistant' and seven 'sensitive' cell lines. We observed stable intracellular glu ...[more]

PMID: 31931281

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Project description:Background & aimsHepatocellular carcinoma (HCC), a leading cause of cancer-related death, is associated with viral hepatitis, non-alcoholic steatohepatitis (NASH), and alcohol-related steatohepatitis, all of which trigger endoplasmic reticulum (ER) stress, hepatocyte death, inflammation, and compensatory proliferation. Using ER stress-prone MUP-uPA mice, we established that ER stress and hypernutrition cooperate to cause NASH and HCC, but the contribution of individual stress effectors, such as activating transcription factor 4 (ATF4), to HCC and their underlying mechanisms of action remained unknown.MethodsHepatocyte-specific ATF4-deficient MUP-uPA mice (MUP-uPA/Atf4Δhep) and control MUP-uPA/Atf4F/F mice were fed a high-fat diet to induce NASH-related HCC, and Atf4F/F and Atf4Δhep mice were injected with diethylnitrosamine to model carcinogen-induced HCC. Histological, biochemical, and RNA-sequencing analyses were performed to identify and define the role of ATF4-induced solute carrier family 7a member 11 (SLC7A11) expression in hepatocarcinogenesis. Reconstitution of SLC7A11 in ATF4-deficient primary hepatocytes and mouse livers was used to study its effects on ferroptosis and HCC development.ResultsHepatocyte ATF4 ablation inhibited hepatic steatosis, but increased susceptibility to ferroptosis, resulting in accelerated HCC development. Although ATF4 activates numerous genes, ferroptosis susceptibility and hepatocarcinogenesis were reversed by ectopic expression of a single ATF4 target, Slc7a11, coding for a subunit of the cystine/glutamate antiporter xCT, which is needed for glutathione synthesis. A ferroptosis inhibitor also reduced liver damage and inflammation. ATF4 and SLC7A11 amounts were positively correlated in human HCC and livers of patients with NASH.ConclusionsDespite ATF4 being upregulated in established HCC, it serves an important protective function in normal hepatocytes. By maintaining glutathione production, ATF4 inhibits ferroptosis-dependent inflammatory cell death, which is known to promote compensatory proliferation and hepatocarcinogenesis. Ferroptosis inhibitors or ATF4 activators may also blunt HCC onset.Impact and implicationsLiver cancer or hepatocellular carcinoma (HCC) is associated with multiple aetiologies. Most HCC aetiologies cause hepatocyte stress and death, as well as subsequent inflammation, and compensatory proliferation, thereby accelerating HCCdevelopment. The contribution of individual stress effectors to HCC and their underlying mechanisms of action were heretofore unknown. This study shows that the stress-responsive transcription factor ATF4 blunts liver damage and cancer development by suppressing iron-dependent cell death (ferroptosis). Although ATF4 ablation prevents hepatic steatosis, it also increases susceptibility to ferroptosis, due to decreased expression of the cystine/glutamate antiporter SLC7A11, whose expression in human HCC and NASH correlates with ATF4. These findings reinforce the notion that benign steatosis may be protective and does not increase cancer risk unless accompanied by stress-induced liver damage. These results have important implications for prevention of liver damage and cancer.

Project description:The cystine/glutamate exchanger (xCT, SLC7A11) is a component of the system Xc amino-acid antiporter that is able to export glutamate and import cysteine into cells. The xCT amino acid exchanger has received a lot of attention, due to the fact that cysteine is an essential substrate for the synthesis of glutathione (GSH), an endogenous antioxidant in cells. The objective of this research was to clone the full-length cDNA of chicken xCT, and to investigate the gene expression of xCT in different tissues, including intestinal segments of broiler chickens during development. The full-length cDNA of chicken xCT (2,703 bp) was obtained from the jejunum by reverse transcription-PCR and sequenced. Homology tests showed that chicken xCT had 80.4%, 80.2%, and 71.2% homology at the nucleotide level with humans, cattle, and rats, respectively. Likewise, amino acid sequence analysis showed that chicken xCT protein is 86.4%, 79.3%, and 75.6% homologous with humans, cattle, and rats, respectively. Additionally, phylogenetic analysis indicated that chicken xCT genes share a closer genetic relationship with humans and cattle, than with rats. The chicken xCT protein has 12 transmembrane helixes, 6 extracellular loops, and 5 intracellular loops. The mRNA of xCT was detected in all tissues, including intestinal segments, in which the mRNA expression of xCT was significantly higher (P < 0.05) within the colon, compared to the jejunum and ileum. During development, a linear pattern of changes regarding the levels of the xCT mRNA was found, indicating that there was an abundance of xCT within the duodenum (P < 0.05). Furthermore, there were changes of the xCT mRNA abundance in the colon during development, which displayed linear and cubic patterns (P < 0.05). These results indicated that xCT is widely expressed both in intestinal segments, as well as other organs that are not associated with nutrient absorption. Further investigation is needed to characterize the functional relevance of xCT activity in oxidative stress and inflammation in the small intestine of broiler chickens.

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XCT (SLC7A11) expression confers intrinsic resistance to physical plasma treatment in tumor cells.

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xCT (SLC7A11) expression confers intrinsic resistance to physical plasma treatment in tumor cells.

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