Cystine-Glutamate Transporter SLC7A11 in Cancer Chemosensitivity and Chemoresistance

Abstract

SLC7A11 (xCT), together with SLC3A2 (4F2hc), encodes the heterodimeric amino acid transport system xc−, which mediates cystine-glutamate exchange and thereby regulates intracellular glutathione levels. We used microarrays to analyze gene expression of transporters in 60 human cancer cell lines used by the National Cancer Institute for drug screening (NCI-60). The expression of SLC7A11 showed significant correlation with that of SLC3A2 (r = 0.66), which in turn correlated with SLC7A5 (r = 0.68), another known partner for SLC3A2, and with T1A-2 (r = 0.60; all P < 0.0001). Linking expression of SLC7A11 with potency of 1,400 candidate anticancer drugs identified 39 showing positive correlations, e.g., amino acid analogue, l-alanosine, and 296 with negative correlations, e.g., geldanamycin. However, no significant correlation was observed with the geldanamycin analogue 17-allylamino, 17-demethoxygeldanamycin (17-AAG). Inhibition of transport system xc− with glutamate or (S)-4-carboxyphenylglycine in lung A549 and HOP-62, and ovarian SK-OV-3 cells, reduced the potency of l-alanosine and lowered intracellular glutathione levels. This further resulted in increased potency of geldanamycin, with no effect on 17-AAG. Down-regulation of SLC7A11 by small interfering RNA affected drug potencies similarly to transport inhibitors. The inhibitor of γ-glutamylcysteine synthetase, buthionine sulfoximine, also decreased intracellular glutathione levels and enhanced potency of geldanamycin, but did not affect l-alanosine. These results indicate that SLC7A11 mediates cellular uptake of l-alanosine but confers resistance to geldanamycin by supplying cystine for glutathione maintenance. SLC7A11 expression could serve as a predictor of cellular response to l-alanosine and glutathione-mediated resistance to geldanamycin, yielding a potential target for increasing chemosensitivity to multiple drugs. https://cancerres.aacrjournals.org/content/65/16/7446

oncotarget removed from pubmed Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncotarget journal . Oncotarget publishes high-impact research papers of general interest and outstanding significance and novelty in all areas of biology and medicine: in translational, basic and clinical research including but not limited to cancer research, oncogenes, oncoproteins and tumor suppressors, signaling pathways as potential targets for therapeutic intervention, shared targets in different diseases (cancer, benign tumors, atherosclerosis, eukaryotic infections, metabolic syndrome and other age-related diseases), chemotherapy, and new therapeutic strategies. After earning her Ph.D. in molecular biology, Zoya was awarded a Fogarty post-doctoral Fellowship from the National Institutes of Health in Bethesda, MD. After successful completion of post-doctoral training, she continued her professional career at George Washington University and Albert Einstein School of Medicine . In 2005 she cofounded the startup company Oncotarget Inc. which is focused on the development of anti-aging and anti-cancer drugs. Her research interests include signal transduction, cell cycle and cellular senescence, and their pharmacological targeting. In 2009 she cofounded the publishing house Impact Journals which specializes in publishing scientific journals. In 2011 she was selected to be a Member of the National Association of Professional Women .
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oncotarget journal impact factor

When general population mention modern medicine, accuracy plays one of the most crucial roles and human lives are literally dependent on it. Hereby, any researches pertaining to medicine are necessary to comply with the highest standards. The issue nowadays is that any results of researches can be published online and used as a reference without being properly verified and approved. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this issue and attempted to create an alternative solution. That’s how a weekly oncology-focused research journal named “Oncotarget” has been established back in 2010. The main principle of this journal is based on Altmetric scores that are used as a quality measure. That assists both readers and authors to quality-check publications with Altmetric Article Reports that create “real-time feedback containing data summary related to a particular publication.” Oncotarget website provides a complete publications list with respective scores above 100 as well as reports discussed above. Mikhail (Misha) Blagosklonny glad to share his new approach and hopes it creates the necessary assistance to anybody, who has interest in oncology.

“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This paper was published back in 2018 by Oncotarget and written by various experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study discusses “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”

The paper has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that majority of readers are aiming to comprehend the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Likewise, the article about melanoma, was used for citations in different news articles 69 times. Besides that, it was mentioned in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their news on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study 

Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This article has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a brief overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get helpful scientific facts. Oncotarget is glad to have the ability to share with online viewers this highly appreciated and high-quality information, that is trustworthy and reliable.

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