Altered Profile of E1-S Transporters in Endometrial Cancer: Lower Protein Levels of ABCG2 and OSTβ and Up-Regulation of SLCO1B3 Expression

Endometrial cancer (EC) is associated with increased estrogen actions. Locally, estrogens can be formed from estrone-sulphate (E1-S) after cellular uptake by organic anion-transporting polypeptides (OATP) or organic anion transporters (OAT). Efflux of E1-S is enabled by ATP Binding Cassette transporters (ABC) and organic solute transporter (OST)αβ. Currently, 19 E1-S transporters are known but their roles in EC are not yet understood. Here, we analysed levels of E1-S transporters in Ishikawa (premenopausal EC), HEC-1-A (postmenopausal EC), HIEEC (control) cell lines, in EC tissue, examined metabolism of steroid precursor E1-S, studied effects of OATPs’ inhibition and gene-silencing on E1-S uptake, and assessed associations between transporters and histopathological data. Results revealed enhanced E1-S metabolism in HEC-1-A versus Ishikawa which could be explained by higher levels of OATPs in HEC-1-A versus Ishikawa, especially 6.3-fold up-regulation of OATP1B3 (SLCO1B3), as also confirmed by immunocytochemical staining and gene silencing studies, lower ABCG2 expression and higher levels of sulfatase (STS). In EC versus adjacent control tissue the highest differences were seen for ABCG2 and SLC51B (OSTβ) which were 3.0-fold and 2.1-fold down-regulated, respectively. Immunohistochemistry confirmed lower levels of these two transporters in EC versus adjacent control tissue. Further analysis of histopathological data indicated that SLCO1B3 might be important for uptake of E1-S in tumours without lymphovascular invasion where it was 15.6-fold up-regulated as compared to adjacent control tissue. Our results clearly indicate the importance of E1-S transporters in EC pathophysiology and provide a base for further studies towards development of targeted treatment.

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Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats

AJP Renal Physiology ◽

10.1152/ajprenal.00473.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. F1599-F1605 ◽

Cited By ~ 64

Author(s):

R. Schneider ◽

C. Sauvant ◽

B. Betz ◽

M. Otremba ◽

D. Fischer ◽

...

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Organic Anion ◽

Organic Anions ◽

Organic Anion Transporters ◽

Protein Levels ◽

Anion Transporters ◽

Pah Clearance ◽

Ischemic Acute Renal Failure

Ischemic acute renal failure (iARF) was described to reduce renal extraction of the organic anion para-aminohippurate (PAH) in humans. The rate-limiting step of renal organic anion secretion is its basolateral uptake into proximal tubular cells. This process is mediated by the organic anion transporters OAT1 and OAT3, which both have a broad spectrum of substrates including a variety of pharmaceutics and toxins. Using a rat model of iARF, we investigated whether impairing the secretion of the organic anion PAH might be associated with downregulation of OAT1 or OAT3. Inulin and PAH clearance was determined starting from 6 up to 336 h after ischemia-reperfusion (I/R) injury. Net secretion of PAH was calculated and OAT1 as well as OAT3 expression was analyzed by RT-PCR and Western blotting. Inulin and PAH clearance along with PAH net secretion were initially diminished after I/R injury with a gradual recovery during follow-up. This initial impairment after iARF was accompanied by decreased mRNA and protein levels of OAT1 and OAT3 in clamped animals compared with sham-operated controls. In correlation to the improvement of kidney function, both mRNA and protein levels of OAT1 and OAT3 were upregulated during the follow-up. Thus decreased expression of OAT1 and OAT3 is sufficient to explain the decline of PAH secretion after iARF. As a result, this may have substantial impact on excretion kinetics and half-life of organic anions. As a consequence, the biological effects of a variety of organic anions may be affected after iARF.

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Nano Ellagic Acid Counteracts Cisplatin-Induced Upregulation in OAT1 and OAT3: A Possible Nephroprotection Mechanism

Molecules ◽

10.3390/molecules25133031 ◽

2020 ◽

Vol 25 (13) ◽

pp. 3031

Author(s):

Thikryat Neamatallah ◽

Nagla El-Shitany ◽

Aymn Abbas ◽

Basma G. Eid ◽

Steve Harakeh ◽

...

Keyword(s):

Ellagic Acid ◽

Organic Anion ◽

Elevated Serum ◽

Protective Role ◽

Oxidative Stress Marker ◽

Protein Levels ◽

Renal Tubular Cells ◽

Anion Transporters ◽

Male Wistar Rats

Cisplatin is an anticancer drug commonly used for solid tumors. However, it causes nephrotoxicity. OAT1 and OAT3 are organic anion transporters known to contribute to the uptake of cisplatin into renal tubular cells. The present study was designed to examine the protective role of ellagic acid nanoformulation (ellagic acid nano) on cisplatin-induced nephrotoxicity in rats, and the role of OAT1/OAT3 in this effect. Four groups of male Wistar rats were used (n = 6): (1) control, (2) cisplatin (7.5 mg/kg single dose, intraperitoneal), (3) cisplatin + ellagic acid nano (1 mg/kg), and (4) cisplatin + ellagic acid nano (2 mg/kg). Nephrotoxic rats treated with ellagic acid nano exhibited a significant reduction in elevated serum creatinine, urea, and oxidative stress marker, malondialdehyde (MDA). Additionally, ellagic acid nano restored renal glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Ellagic acid nano improved the histopathological changes induced by cisplatin, such as tubular dilatation, necrosis, and degeneration. Interestingly, OAT1 and OAT3 showed significantly lower expression at both mRNA and protein levels following ellagic acid nano treatment relative to the cisplatin-exposed group. These findings reveal a potential inhibitory role of ellagic acid antioxidant on OAT1 and OAT3 expression and thus explains its nephroprotective effect against cisplatin nephrotoxicity.

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High‐risk endometrial cancer proteomic profiling reveals that FBXW7 mutation alters L1CAM and TGM2 protein levels

Cancer ◽

10.1002/cncr.33567 ◽

2021 ◽

Author(s):

Mary Ellen Urick ◽

Eun‐Jeong Yu ◽

Daphne W. Bell

Keyword(s):

Endometrial Cancer ◽

High Risk ◽

Proteomic Profiling ◽

Protein Levels

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Tenofovir and Severe Symptomatic Hypophosphatemia

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/2324709619848796 ◽

2019 ◽

Vol 7 ◽

pp. 232470961984879 ◽

Cited By ~ 2

Author(s):

Asim Kichloo ◽

Savneek Singh Chugh ◽

Sanjeev Gupta ◽

Jay Panday ◽

Ghazaleh Goldar

Keyword(s):

Renal Damage ◽

Organic Anion ◽

Significant Risk ◽

Anion Transporters ◽

Immunodeficiency Virus ◽

Tubular Lumen ◽

Associated Proteins ◽

Proximal Tubular ◽

Renal Tubular ◽

Initial Results

Tenofovir is a broadly used drug used for the treatment of human immunodeficiency virus (HIV). Although the initial results of the clinical trials supported the renal safety of Tenofovir, clinical use of it has caused a low, albeit a significant, risk of renal damage either in the form of AKI or CKD. The pathophysiology has been linked to the effect of this medication on the proximal tubular cell. Although the exact mechanism is unknown, studies have suggested that Tenofovir accumulates in proximal tubular cells which are rich in mitochondria. It is both filtered in the glomerulus and actively secreted in the tubules for elimination and is excreted unchanged in the urine. Studies have shown an active transportation of 20-30% of this drug into the renal proximal tubule (PCT) cells via the organic anion transporters in the baso-lateral membrane (primarily hOAT1, and OAT3 to a lesser extent) and ultimate excretion of the drug into the tubular lumen via the transporters in the proximal tubular apical membrane MRP4 and MRP2 (multidrug resistance-associated proteins 2 & 4). Subsequently, the mitochondrial injury caused by Tenofovir can lead to the development of Fanconi’s syndrome which causes renal tubular acidosis, phosphaturia, aminoaciduria, glucosuria with normoglycemia, and tubular proteinuria. Here we present a case where Tenofovir treatment resulted in severe hypophosphatemia requiring hospitalization for parentral phosphate repletion.

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