estrone-sulfate and estradiol-3-17-disulfate

Adrenocortical carcinoma (ACC) is a rare tumor with variable prognosis even within the same tumor stage. Cancer-related sex hormones and their sulfated metabolites in body fluids can be used as tumor markers. The role of steroid sulfation in ACC has not yet been studied. MALDI mass spectrometry imaging (MALDI-MSI) is a novel tool for tissue-based chemical phenotyping.. We performed phenotyping of formalin-fixed, paraffin-embedded tissue samples from 72 ACC by MALDI-MSI at a metabolomics level.. Tumoral steroid hormone metabolites-estradiol sulfate [hazard ratio (HR) 0.26; 95% CI, 0.10-0.69;. MALDI-MSI provides novel insights into the pathophysiology of ACC. Steroid hormone sulfation may be used for prognostication and treatment stratification. Sulfation-related metabolic reprogramming may be of relevance also in conditions beyond the rare ACC and can be directly investigated by the use of MALDI-MSI.

Topics: Adolescent; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Biomarkers, Tumor; Child; Estradiol; Estrone; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Steroids; Sulfotransferases; Young Adult

Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters which play critical roles in the body disposition of clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories. hOAT4 is expressed in the placenta and kidney. In the current study, we stably transfected hOAT4 into human placental BeWo cells and the functional properties of hOAT4 and its regulation were investigated in these cells. hOAT4-mediated uptake of estrone sulfate, a protypical organic anion for hOAT4, was dose- and time-dependent, and saturable (Km=4.2 microM). The substrate specificity of hOAT4 includes various steroid sulfates, such as beta-estradiol-3,17-disulfate, 17-beta-estradiol-3-sulfate, beta-estradiol-3-sulfate, and dehydroepiandrosterone-3-sulfate (DHEAS), but does not include p-aminohippuric acid (PAH) and tetraethylammonium (TEA). Pre-incubation of hOAT4-expressing BeWo cells with phorbol 12-myristate 13-acetate (PMA) and phorbol 12,13-dibutyrate (PDBu), both of which are protein kinase C (PKC) activators, acutely inhibited the transport activity. The inhibition by PDBu resulted in a decreased Vmax without significant affecting the Km. Establishment of hOAT4-expressing BeWo cells provided useful tool for further pharmacological and molecular biological studies of placental transport of organic anions mediated by this carrier.

Topics: Cell Line; Dehydroepiandrosterone Sulfate; Enzyme Activation; Estradiol; Estrone; Humans; Kinetics; Organic Anion Transporters, Sodium-Independent; Phorbol 12,13-Dibutyrate; Placenta; Protein Kinase C; Tetradecanoylphorbol Acetate; Transfection