SLC10A7 represents an orphan member of the Solute Carrier Family SLC10. Recently, mutations in the human SLC10A7 gene were associated with skeletal dysplasia, amelogenesis imperfecta, and decreased bone mineral density. However, the exact molecular function of SLC10A7 and the mechanisms underlying these pathologies are still unknown. For this reason, the role of SLC10A7 on intracellular calcium signaling was investigated. SLC10A7 protein expression was negatively correlated with store-operated calcium entry (SOCE) via the plasma membrane. Whereas SLC10A7 knockout HAP1 cells showed significantly increased calcium influx after thapsigargin, ionomycin and ATP/carbachol treatment, SLC10A7 overexpression reduced this calcium influx. Intracellular Ca²⁺ levels were higher in the SLC10A7 knockout cells and lower in the SLC10A7-overexpressing cells. The SLC10A7 protein co-localized with STIM1, Orai1, and SERCA2. Most of the previously described human SLC10A7 mutations had no effect on the calcium influx and thus were confirmed to be functionally inactive. In the present study, SLC10A7 was established as a novel negative regulator of intracellular calcium signaling that most likely acts via STIM1, Orai1 and/or SERCA2 inhibition. Based on this, SLC10A7 is suggested to be named as negative regulator of intracellular calcium signaling (in short: RCAS).

Background: Intestinal ischemia reperfusion (IR) is associated with morbidity and mortality. We first examined the role of levosimendan in the protection of intestine after mesenteric IR. Methods: The rats were divided into six groups: (1) Control group; (2) Levosimendan group; (3) Ischemia group (60 min of occlusion); (4) IR group (60 min of occlusion and then 60 min reperfusion); (5) IR + 1 mg/kg levosimendan group: Levosimendan was given intraperitonally 30 min prior to the ischemia; (6) IR + 2 mg/kg levosimendan group. Results: The levels of TNF-α, IL-6, and IL-1β were found to have increased in the IR group. The serum levels of TNF-α, IL-6, and IL-1β were found to have decreased as a result of the administration of both doses of levosimendan in the IR. Relative TNF-α and NFκB mRNA levels was decreased by administration of both doses of levosimendan in the IR. SOD activity and GSH levels for IR group were lower than, and 8-ISO levels were higher than, those of the sham-operated rat and ischemia alone group. Conclusions: Both doses of levosimendan had preventive effects on the alterations that occurred in the intestinal tissues after IR. Levosimendan administration attenuated in reperfusion injury of intestine and consequently protects intestinal mucosa and oxidant-antioxidant balance of ileum.

The sodium-dependent organic anion transporter (SOAT, gene symbol SLC10A6) specifically transports 3′- and 17′-monosulfated steroid hormones, such as estrone sulfate and dehydroepiandrosterone sulfate, into specific target cells. These biologically inactive sulfo-conjugated steroids occur in high concentrations in the blood circulation and serve as precursors for the intracrine formation of active estrogens and androgens that contribute to the overall regulation of steroids in many peripheral tissues. Although SOAT expression has been detected in several hormone-responsive peripheral tissues, its quantitative contribution to steroid sulfate uptake in different organs is still not completely clear. Given this fact, the present review provides a comprehensive overview of the current knowledge about the SOAT by summarizing all experimental findings obtained since its first cloning in 2004 and by processing SOAT/SLC10A6-related data from genome-wide protein and mRNA expression databases. In conclusion, despite a significantly increased understanding of the function and physiological significance of the SOAT over the past 20 years, further studies are needed to finally establish it as a potential drug target for endocrine-based therapy of steroid-responsive diseases such as hormone-dependent breast cancer.

Peripheral tissues such as skin and adipose tissue play a crucial role in the intracrine formation of sex steroid hormones, complementing the endocrine and paracrine systems. These mechanisms involve the conversion of dehydroepiandrosterone (DHEA) and its sulfated form—DHEAS—into potent androgenic and estrogenic hormones. In vitro studies using tissue-specific cell lines are essential for unraveling the complex intracrine synthesis of these hormones. This study examined the formation of DHEA, androstenedione (A4), testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) from DHEAS in four cell lines: MCF-7 breast cancer cells, HaCaT keratinocytes, human dermal fibroblasts (HDF), and 3T3-L1 preadipocytes and mature adipocytes, using liquid chromatography–mass spectrometry (LC-MS/MS). MCF-7 cells converted DHEAS to DHEA, A4, T, E2, and DHT, while HaCaT cells produced all these steroids except DHT. Mature 3T3-L1 adipocytes produced DHEA, A4, T, and DHT. By contrast, HDF and 3T3-L1 preadipocytes converted DHEAS only to DHEA and A4. This study highlights the vital role of peripheral tissues, such as skin and adipose tissue, for the intracrine formation of sex hormones and underlines the crucial role of in vitro cell culture models to analyze such effects. The data shed light on the significant impact of androgen metabolism in skin and adipose tissue, which is of great relevance for aging, wound healing, obesity, and lipid metabolism.

Intracrine estrogen formation from adrenal precursors such as dehydroepiandrosterone sulfate (DHEAS) plays a critical role in sustaining estrogen receptor (ER)-positive breast cancer cell proliferation, particularly in postmenopausal women. The sodium-dependent organic anion transporter (SOAT, gene symbol SLC10A6 ) facilitates the cellular uptake of sulfated steroids, thereby making these precursors available for local estrogen biosynthesis. However, the impact of SOAT inhibition on intracrine estrogen metabolism in breast cancer remains unclear. We investigated the effects of pharmacological SOAT inhibition on SOAT-mediated DHEAS transport, cell proliferation and intracrine estradiol synthesis in SOAT-overexpressing MCF-7 breast cancer cells (MCF-7_SOAT). These MCF-7_SOAT cells were treated with the SOAT inhibitor S1647, as well as two newly synthesized derivatives (compounds 12 and 24) that exhibit enhanced selectivity and potency. DHEAS uptake and downstream steroid metabolism were quantified using LC–MS/MS, while DHEAS-induced cell proliferation was analyzed using [³H]thymidine incorporation. SOAT inhibition markedly reduced sodium-dependent DHEAS uptake, resulting in decreased intracellular estradiol synthesis and suppression of estrogen-dependent proliferation without cytotoxicity. These findings confirm that SOAT is a critical upstream regulator of intracrine estrogen biosynthesis in breast cancer cells and highlight compounds 12 and 24 as promising candidates for further preclinical development aimed at reducing local estrogen production.