Differential Expression of OATP1B3 Mediates Unconjugated Testosterone Influx

Sissung, Tristan M.; Ley, Ariel M.; Strope, Jonathan D.; McCrea, Edel M.; Beedie, Shaunna; Peer, Cody J.; Shukla, Suneet; Velkinburgh, Jennifer C. van; Reece, Kelie; Troutman, Sarah M.; Campbell, Tessa J; Fernandez, Elena V.; Huang, Phoebe; Smith, Jordan L.; Thakkar, Nilay; Venzon, David; Brenner, Stefan; Lee, Wooin; Merino, María J.; Luo, Ji; Jäger, Walter; Price, Douglas K.; Chau, Cindy H.; Figg, William D.

doi:10.1158/1541-7786.mcr-16-0477

Cited by 17 publications

(37 citation statements)

References 32 publications

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“…16 In addition, recent work indicates that organic anion-transporting polypeptide (OATP)1B3, an anionic lowaffinity transporter for eg, estrone-3-sulfate (E1S) and DHEAS, could also transport testosterone at 20 uM concentrations. 17 Here we present additional support for findings that challenge the orthodoxy of passive, nonspecific diffusion as the only entry mechanism of testosterone into PC cells. We found at the prostate cell level the same phenomenon as described in seminiferous tubules and rete testis, [12][13][14][15] in that testosterone followed a concentration gradient but was saturable (thus specific) and temperature-dependent.…”

Section: Introductionsupporting

confidence: 76%

“…While less studied, neutral unconjugated steroid hormones, eg, estrogen, progesterone, cortisol, and thyroid hormone, have also been shown to enter cells by transporter-mediated uptake. 20,[51][52][53][54][55] In PC, the cell membrane protein OATP1B3 has been shown to transport testosterone into cells; 17,26 however, concentrations were 1000× higher than those used here to utilize this transporter, which is in line with the concentrations needed for the transport of conjugated steroids, such as DHEAS and E1S, by OATPs. 25 Although the molecular identity of the carrier studied here remains elusive, our results provide a starting point for further characterization.…”

Section: Discussionmentioning

confidence: 63%

“…Recent studies have suggested that OATP1B3, an anionic lowaffinity solute transporter for compounds such as E1S and DHEAS, could also transport testosterone. 17,25,26 Therefore, we established OATP1B3 overexpressing LNCaP lines and examined testosterone entry into the cells. 27 After administration of 20 nM 3…”

Section: Assessment Of Oatps In Prostate Cancer Cell Testosterone Tmentioning

confidence: 99%

“…A fourth model involves energy‐dependent, ie, active transport for testosterone, and is supported by studies of epididymal epithelium in the rat . In addition, recent work indicates that organic anion‐transporting polypeptide (OATP)1B3, an anionic low‐affinity transporter for eg, estrone‐3‐sulfate (E1S) and DHEAS, could also transport testosterone at 20 uM concentrations …”

Section: Introductionmentioning

confidence: 99%

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Testosterone accumulation in prostate cancer cells is enhanced by facilitated diffusion

et al. 2019

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Background Testosterone is a driver of prostate cancer (PC) growth via ligand‐mediated activation of the androgen receptor (AR). Tumors that have escaped systemic androgen deprivation, castration‐resistant prostate cancers (CRPC), have measurable intratumoral levels of testosterone, suggesting that a resistance mechanism still depends on androgen‐simulated growth. However, AR activation requires an optimal intracellular concentration of androgens, a situation challenged by low circulating testosterone concentrations. Notably, PC cells may optimize their androgen levels by regulating the expression of steroid metabolism enzymes that convert androgen precursors into androgens. Here we propose that testosterone entry into the cell could be another control point. Methods To determine whether testosterone enters cells via a transporter, we performed in vitro 3H‐testosterone uptake assays in androgen‐dependent LNCaP and androgen and AR‐independent PC3 cells. To determine if the uptake mechanism depended on a concentration gradient, we modified UGT2B17 levels in LNCaP cells and measured androgen levels by liquid‐liquid extraction–mass spectrometry. We also analyzed CRPC metastases for expression of AKR1C3 to determine whether this enzyme that converts adrenal androgens to testosterone was present in the tumor stroma (microenvironment) in addition to its expression in the tumor epithelium. Results Testosterone uptake followed a concentration gradient but unlike in passive diffusion, was saturable and temperature‐dependent, thus suggesting facilitated transport. Suppression of UGT2B17 to abrogate a testosterone gradient reduced testosterone transport while overexpression of the enzyme enhanced it. The facilitated transport suggests a paracrine route of testosterone uptake for maintaining optimal intracellular levels. We found that AKR1C3 was expressed in the tumor microenvironment of CRPC metastases in addition to epithelial cells and the pattern of relative abundance of the enzyme in epithelium vs stroma varied substantially between the metastatic sites. Conclusions Our findings suggest that in addition to testosterone transport and metabolism by tumor epithelium, testosterone could also be produced by components of the tumor microenvironment. Facilitated testosterone uptake by tumor cells supports a cell nonautonomous mechanism for testosterone signaling in CRPC.

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Section: Introductionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 63%

Section: Assessment Of Oatps In Prostate Cancer Cell Testosterone Tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Testosterone accumulation in prostate cancer cells is enhanced by facilitated diffusion

et al. 2019

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“…From all established members of the OATP family, lt-OATP1B3 has been extensively characterized for its function as an uptake transporter for several established OATP substrates and for its role in paclitaxel uptake (van de Steeg et al, 2013 ). Because the OATP variant has poor transport capacity compared to the lt-OATP1B3, paclitaxel uptake by ct-OATP1B3 into ovarian cancer cells is unlikely (Thakkar et al, 2013 ; Sun et al, 2014 ; Furihata et al, 2015 ; Sissung et al, 2017 ; Alam et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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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Understanding and targeting resistance mechanisms in cancer

Lei

Teng

Wurpel

et al. 2023

MedComm

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Resistance to cancer therapies has been a commonly observed phenomenon in clinical practice, which is one of the major causes of treatment failure and poor patient survival. The reduced responsiveness of cancer cells is a multifaceted phenomenon that can arise from genetic, epigenetic, and microenvironmental factors. Various mechanisms have been discovered and extensively studied, including drug inactivation, reduced intracellular drug accumulation by reduced uptake or increased efflux, drug target alteration, activation of compensatory pathways for cell survival, regulation of DNA repair and cell death, tumor plasticity, and the regulation from tumor microenvironments (TMEs). To overcome cancer resistance, a variety of strategies have been proposed, which are designed to enhance the effectiveness of cancer treatment or reduce drug resistance. These include identifying biomarkers that can predict drug response and resistance, identifying new targets, developing new targeted drugs, combination therapies targeting multiple signaling pathways, and modulating the TME. The present article focuses on the different mechanisms of drug resistance in cancer and the corresponding tackling approaches with recent updates. Perspectives on polytherapy targeting multiple resistance mechanisms, novel nanoparticle delivery systems, and advanced drug design tools for overcoming resistance are also reviewed.

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Differential Expression of OATP1B3 Mediates Unconjugated Testosterone Influx

Cited by 17 publications

References 32 publications

Testosterone accumulation in prostate cancer cells is enhanced by facilitated diffusion

Testosterone accumulation in prostate cancer cells is enhanced by facilitated diffusion

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

Understanding and targeting resistance mechanisms in cancer

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