LST-3TM12 is a member of the OATP1B family and a functional transporter

Malagnino, Vanessa; Hußner, Janine; Seibert, Isabell; Stolzenburg, Antje; Sager, Christoph P.; Schwabedissen, Henriette E. Meyer zu

doi:10.1016/j.bcp.2017.12.012

Cited by 20 publications

(37 citation statements)

References 29 publications

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“…In all samples of our cohort we detected the expression of SLCO1B7 , which was previously considered a pseudogene but has recently been characterized for protein coding (Malagnino et al, 2018 ). This was a notable finding as the expression of SLCO1B7 in normal tissues is considered to be high only in liver ( https://www.ncbi.nlm.nih.gov/gene/338821 ).…”

Section: Resultsmentioning

confidence: 98%

“…Interestingly, a joint activity for OATP2B1 with another ABC-efflux pump, ABCG2 (BCRP), was described in a study on the human placenta, where the two transporters were thought to mediate uptake and excretion of sulfated estrogen precursors (Grube et al, 2007 ). However, considering that OATP2B1 may be an uptake transporter for estrogens, it has been suggested that a number of OATPs (OATP1A2, OATP1B1, OATP1B3, OATP1C1, OATP3A1, OATP4A1, and OATP5A1) (Stieger and Hagenbuch, 2014 ) and also LST-3TM12 and OATP6A1 (Patik et al, 2015 ; Malagnino et al, 2018 ) are capable of transporting estrogen precursors. Furthermore, the substrate specificity for E1S and DHEA-S differs widely between individual members and cells investigated.…”

Section: Discussionmentioning

confidence: 99%

“…A recent in silico analysis revealed that trans-splicing of SLCO1B7 and SLCO1B3 produced a novel OATP family 1 member, LST-3TM12. Furthermore, heterologous expression of SLCO1B3 and SLCO1B7 in HeLa cells leads to LST-3TM12 protein expression, resulting in an increased cellular accumulation of E2-glucuronide and DHEA-S (Malagnino et al, 2018 ). However, we did not observe significant co-expression of SLCO1B7 with SLCO1B3 in our cohort, but co-expression with the cancer-specific variant might be possible (Furihata et al, 2015 ; Thakkar et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

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Clinical Significance of Organic Anion Transporting Polypeptide Gene Expression in High-Grade Serous Ovarian Cancer

et al. 2018

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High-grade serous ovarian cancer (HGSOC) is considered the most deadly and frequently occurring type of ovarian cancer and is associated with various molecular compositions and growth patterns. Evaluating the mRNA expression pattern of the organic anion transporters (OATPs) encoded by SLCO genes may allow for improved stratification of HGSOC patients for targeted invention. The expression of SLCO mRNA and genes coding for putative functionally related ABC-efflux pumps, enzymes, pregnane-X-receptor, ESR1 and ESR2 (coding for estrogen receptors ERα and ERß) and HER-2 were assessed using RT-qPCR. The expression levels were assessed in a cohort of 135 HGSOC patients to elucidate the independent impact of the expression pattern on the overall survival (OS). For identification of putative regulatory networks, Graphical Gaussian Models were constructed from the expression data with a tuning parameter K varying between meaningful borders (Pils et al., 2012; Auer et al., 2015, 2017; Kurman and Shih Ie, 2016; Karam et al., 2017; Labidi-Galy et al., 2017; Salomon-Perzynski et al., 2017; Sukhbaatar et al., 2017). The final value used (K = 4) was determined by maximizing the proportion of explained variation of the corresponding LASSO Cox regression model for OS. The following two networks of directly correlated genes were identified: (i) SLCO2B1 with ABCC3 implicated in estrogen homeostasis; and (ii) two ABC-efflux pumps in the immune regulation (ABCB2/ABCB3) with ABCC3 and HER-2. Combining LASSO Cox regression and univariate Cox regression analyses, SLCO5A1 coding for OATP5A1, an estrogen metabolite transporter located in the cytoplasm and plasma membranes of ovarian cancer cells, was identified as significant and independent prognostic factor for OS (HR = 0.68, CI 0.49–0.93; p = 0.031). Furthermore, results indicated the benefits of patients with high expression by adding 5.1% to the 12.8% of the proportion of explained variation (PEV) for clinicopathological parameters known for prognostic significance (FIGO stage, age and residual tumor after debulking). Additionally, overlap with previously described signatures that indicated a more favorable prognosis for ovarian cancer patients was shown for SLCO5A1, the network ABCB2/ABCB3/ABCC4/HER2 as well as ESR1. Furthermore, expression of SLCO2A1 and PGDH, which are important for PGE2 degradation, was associated with the non-miliary peritoneal tumor spreading. In conclusion, the present findings suggested that SLCOs and the related molecules identified as potential biomarkers in HGSOC may be useful for the development of novel therapeutic strategies.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Clinical Significance of Organic Anion Transporting Polypeptide Gene Expression in High-Grade Serous Ovarian Cancer

et al. 2018

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“…The OATP1B family of organic anion transporting polypeptides is the most famous in terms of uptake transporters influencing the in vivo handling of drugs. This subfamily consists of three members namely OATP1B1, OATP1B3, and OATP1B3-1B7 readthrough [10][11][12]. These transporters are highly abundant in the liver, where they have a crucial role in drug metabolism and elimination.…”

Section: Oatp1b Transportersmentioning

confidence: 99%

Uptake Transporters of the SLC21, SLC22A, and SLC15A Families in Anticancer Therapy—Modulators of Cellular Entry or Pharmacokinetics?

Brecht

Schäfer

Schwabedissen

2020

Cancers

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Solute carrier transporters comprise a large family of uptake transporters involved in the transmembrane transport of a wide array of endogenous substrates such as hormones, nutrients, and metabolites as well as of clinically important drugs. Several cancer therapeutics, ranging from chemotherapeutics such as topoisomerase inhibitors, DNA-intercalating drugs, and microtubule binders to targeted therapeutics such as tyrosine kinase inhibitors are substrates of solute carrier (SLC) transporters. Given that SLC transporters are expressed both in organs pivotal to drug absorption, distribution, metabolism, and elimination and in tumors, these transporters constitute determinants of cellular drug accumulation influencing intracellular drug concentration required for efficacy of the cancer treatment in tumor cells. In this review, we explore the current understanding of members of three SLC families, namely SLC21 (organic anion transporting polypeptides, OATPs), SLC22A (organic cation transporters, OCTs; organic cation/carnitine transporters, OCTNs; and organic anion transporters OATs), and SLC15A (peptide transporters, PEPTs) in the etiology of cancer, in transport of chemotherapeutic drugs, and their influence on efficacy or toxicity of pharmacotherapy. We further explore the idea to exploit the function of SLC transporters to enhance cancer cell accumulation of chemotherapeutics, which would be expected to reduce toxic side effects in healthy tissue and to improve efficacy.

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“…thyroid hormones, bilirubin, bile acids) and are important in the disposition of several drugs and other xenobiotics. Up to now, 12 human OATPs have been identified, of which the liver‐specific OATP1B1, encoded by the SLCO1B1 gene, is best characterized . Loss of function mutations of OATP1B1 (and OATP1B3) have been associated with the Rotor syndrome, a rare, benign disease presenting with conjugated and unconjugated hyperbilirubinemia .…”

Section: Introductionmentioning

confidence: 99%

microRNA‐206 modulates the hepatic expression of the organic anion‐transporting polypeptide 1B1

Saadany

Rosmalen

Gai

et al. 2019

Liver International

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Background & Aims: The organic anion-transporting polypeptide 1B1 (OATP1B1) is an anion exchanger expressed at the hepatocyte sinusoidal membrane, which mediates the uptake of several endogenous metabolites and drugs. OATP1B1 expression level and activity are major sources of inter-patient variability of pharmacokinetics and pharmacodynamics of several drugs. Besides the genotype, factors that contribute to the inter-individual variability in OATP1B1 expression level are practically unknown. The aim of this work was to uncover novel epigenetic mechanisms of OATP1B1 regulation. Methods: A functional screening strategy to assess the effect of microRNAs on the uptake of estrone-3-sulphate, an OATP1B1 substrate, into human hepatocellular carcinoma (Huh-7) cells was used. microRNA-206 (miR-206) expression in human liver tissues was measured by real-time RT-PCR. OATP1B1 expression in Huh-7 and in human liver tissues was assessed by real-time RT-PCR, Western blotting and immunostaining. The mRNA-miRNA interaction was assessed by reporter assay. Results: miR-206 mimic repressed mRNA and protein expression of OATP1B1 in Huh-7 cells. The intracellular accumulation of estrone-3-sulphate was reduced by 30% in cells overexpressing miR-206. The repressive effect of miR-206 on the activity of the firefly luciferase gene 2 under the control of the OATP1B1 3' untranslated region was lost upon deletion of the predicted miR-206 binding site. Hepatic miR-206 level negatively correlated with OATP1B1 mRNA and protein levels extracted from normal human liver tissues. Conclusions: miR-206 exerts a suppressive effect on OATP1B1 expression by an epigenetic mechanism. Individuals with high hepatic levels of miR-206 appear to display lower level of OATP1B1. K E Y W O R D S epigenetics, liver, microRNA-206, OATP1B1 | 2351 EL SAADANY Et AL.

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LST-3TM12 is a member of the OATP1B family and a functional transporter

Cited by 20 publications

References 29 publications

Clinical Significance of Organic Anion Transporting Polypeptide Gene Expression in High-Grade Serous Ovarian Cancer

Clinical Significance of Organic Anion Transporting Polypeptide Gene Expression in High-Grade Serous Ovarian Cancer

Uptake Transporters of the SLC21, SLC22A, and SLC15A Families in Anticancer Therapy—Modulators of Cellular Entry or Pharmacokinetics?

microRNA‐206 modulates the hepatic expression of the organic anion‐transporting polypeptide 1B1

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