Review of estrone sulfatase and its inhibitors--an important new target against hormone dependent breast cancer

A high proportion (approximately 40%) of breast cancers are hormone dependent. The female hormones estradiol and androstenediol are believed to play a key role in the initiation and promotion of this disease. In the fight against hormone dependent breast cancers, extensive research has been undertaken to produce compounds which are potent inhibitors against the cytochrome P-450 enzyme aromatase (AR), which converts the C19 androgens to the C18 estrogens. However, the administration of AR inhibitors alone has failed to produce the expected decrease in plasma levels of estrone. The major impetus to the development of steroid sulfatase inhibitors has therefore been the realisation that in order to improve therapeutic response for women with hormone-dependent breast cancer, not only must the AR enzyme be inhibited, but also the synthesis of estrogens via alternative routes. The steroid sulfatase enzyme regulates the formation of estrone (which can subsequently be converted to the potent estrogen estradiol) from estrone sulfate, a steroid conjugate present in high concentrations in tissue and blood in women with breast cancer. The sulfatase enzyme system also controls the formation of dehydroepiandrosterone (DHEA) from the DHEA-sulfate. This is important since DHEA can be converted to 5-androstene-3 beta,17 beta-diol, which possesses estrogenic properties capable of stimulating the growth of breast cancer cells in vitro and in vivo. Considerable progress has been made in recent years in the development of a number of potent steroid/estrone sulfatase inhibitors, as such both steroidal and non-steroidal compounds have been considered and a number of highly potent inhibitors have been produced and evaluated against what is now considered a crucial enzyme in the fight against hormone dependent breast cancer. The review therefore considers the work that has been undertaken to date, as well as possible future development with respect to dual inhibitors of both estrone sulfatase and AR.     

Structure-activity relationships of 17alpha-derivatives of estradiol as inhibitors of steroid sulfatase

The steroid sulfatase or steryl sulfatase is a microsomal enzyme widely distributed in human tissues that catalyzes the hydrolysis of sulfated 3-hydroxy steroids to the corresponding free active 3-hydroxy steroids. Since androgens and estrogens may be synthesized inside the cancerous cells starting from dehydroepiandrosterone sulfate (DHEAS) and estrone sulfate (E(1)S) available in blood circulation, the use of therapeutic agents that inhibit steroid sulfatase activity may be a rewarding approach to the treatment of androgeno-sensitive and estrogeno-sensitive diseases. In the present study, we report the chemical synthesis and biological evaluation of a new family of steroid sulfatase inhibitors. The inhibitors were designed by adding an alkyl, a phenyl, a benzyl, or a benzyl substituted at position 17alpha of estradiol (E(2)), a C18-steroid, and enzymatic assays were performed using the steroid sulfatase of homogenized JEG-3 cells or transfected in HEK-293 cells. We observed that a hydrophobic substituent induces powerful inhibition of steroid sulfatase while a hydrophilic one was weak. Although a hydrophobic group at the 17alpha-position increased the inhibitory activity, the steric factors contribute to the opposite effect. As exemplified by 17alpha-decyl-E(2) and 17alpha-dodecyl-E(2), a long flexible side chain prevents adequate fitting into the enzyme catalytic site, thus decreasing capacity to inhibit the steroid sulfatase activity. In the alkyl series, the best compromise between hydrophobicity and steric hindrance was obtained with the octyl group (IC(50) = 440 nM), but judicious branching of side chain could improve this further. Benzyl substituted derivatives of estradiol were better inhibitors than alkyl analogues. Among the series of 17alpha-(benzyl substituted)-E(2) derivatives studied, the 3'-bromobenzyl, 4'-tert-butylbenzyl, 4'-butylbenzyl, and 4'-benzyloxybenzyl groups provided the most potent inhibition of steroid sulfatase transformation of E(1)S into E(1) (IC(50) = 24, 28, 25, and 22 nM, respectively). As an example, the tert-butylbenzyl group increases the ability of the E(2) nucleus to inhibit the steroid sulfatase by 3000-fold, and it also inhibits similarly the steroid sulfatase transformations of both natural substrates, E(1)S and DHEAS. Interestingly, the newly reported family of steroid sulfatase inhibitors acts by a reversible mechanism of action that is different from the irreversible mechanism of the known inhibitor estrone sulfamate (EMATE).     

First dual aromatase-steroid sulfatase inhibitors

Aromatase inhibitors in clinical use block the biosynthesis of estrogens. Hydrolysis of estrone 3-sulfate by steroid sulfatase is an important additional source of tumor estrogen, and blockade of both enzymes should provide a more effective endocrine therapy. Sulfamoylated derivatives of the aromatase inhibitor YM511 inhibited sulfatase and aromatase in JEG-3 cells with respective IC(50) values of 20-227 and 0.82-100 nM (cf. letrozole, 0.89 nM). One dual inhibitor was potent against both enzymes in vivo, validating the concept.     

Potent inhibition of steroid sulfatase activity by 3-O-sulfamate 17alpha-benzyl(or 4'-tert-butylbenzyl)estra-1,3,5(10)-trienes: combination of two substituents at positions C3 and c17alpha of estradiol.

Steroid sulfates are precursors of hormones that stimulate androgen- and estrogen-dependent cancers. Thus, steroid sulfatase, the enzyme that catalyzes conversion of DHEAS and E1S to the corresponding unconjugated steroids DHEA and E1, appears to be one of the key enzymes regulating the level of active androgenic and estrogenic steroids. Since 17alpha-substituted benzylestradiols and 3-O-sulfamate estrone (EMATE) represent two families of steroid sulfatase inhibitors that probably act through different mechanisms, we synthesized compounds 3-O-sulfamate 17alpha-benzylestradiol (4) and 3-O-sulfamate 17alpha-(tert-butylbenzyl)estradiol (5) that contain two kinds of substituents on the same molecule. In our enzymatic assay using a homogenate of human embryonal (293) cells transfected with steroid sulfatase, compounds 4 and 5 were found to be more potent inhibitors than already known steroid sulfatase inhibitors that have only a C17alpha-substituent or only a C3-sulfamate group (EMATE). The IC50 values of 4 and 5 were, respectively, 0.39 and 0.15 nM for the transformation of E1S to E1 and 4.1 and 1.4 nM for the transformation of DHEAS to DHEA. Compound 5 inhibited the steroid sulfatase activity in intact transfected (293) cell culture assays by inactivating the enzyme activity. Compound 5 also inactivates the steroid sulfatase activity at lower concentration than EMATE in microsomes of transfected (293) cells. In this assay, an excess of natural substrate E1S protects enzyme against inactivation by 5 or EMATE. Furthermore, the unsulfamoylated analogue of 5, compound 3, did not inactivate the steroid sulfatase.     

Synthesis and biological activity of the superestrogen (E)-17-oximino-3-O-sulfamoyl-1,3,5(10)-estratriene: x-ray crystal structure of (E)-17-oximino-3-hydroxy-1,3,5(10)-estratriene.

Steroid sulfatases regulate the formation of estrogenic steroids which can support the growth of endocrine-dependent breast tumors. Therefore, the development of potent steroid sulfatase inhibitors could have considerable therapeutic potential. Several such inhibitors have now been developed including estrone 3-O-sulfamate (EMATE, 1), which shows potent active site-directed inhibition. However, EMATE was subsequently shown to be also a potent estrogen. In an attempt to reduce the estrogenicity while retaining the potent sulfatase inhibitory properties associated with this type of molecule, (E)-17-oximino-3-O-sulfamoyl-1,3,5(10)-estratriene (5) (estrone oxime 3-O-sulfamate, OMATE) was synthesized. The X-ray crystal structure of (E)-17-oximino-3-hydroxy-1,3,5(10)-estratriene (4) (estrone oxime) demonstrated the presence of only one geometrical isomer [anti-isomer, (E)]. OMATE potently inhibited estrone sulfatase (E1-STS) activity and was similar to EMATE (>99% inhibition at 0.1 microM in MCF-7 breast cancer cells). It was also evaluated in vivo for its estrogenicity and ability to inhibit sulfatase activity. While it was equipotent with EMATE in vivo as a sulfatase inhibitor, it surprisingly had a stimulatory effect on uterine growth in ovariectomized rats about 1.5-fold greater than that of EMATE. Thus, OMATE possesses potential as a superestrogen and modification at C-17 is identified as a useful route for enhancement of estrogenicity in sulfamate-based estrogens.     

Recent developments of steroid sulfatase inhibitors as anti-cancer agents

The steroid sulfatase (STS) enzyme plays a pivotal role in the formation of biologically active steroid hormones. Its involvement in the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, is an important step in the formation of estradiol and androstenediol, both of which are estrogenic steroids that can stimulate tumor growth. Consequently, as STS is widely distributed throughout the entire body, it has a substantial influence on hormone-dependent cancer mitogenesis. It is a useful prognostic marker of disease as a significant majority of breast tumors over-express the enzyme and there are indications of STS having a role in prostate cancer. This knowledge has led to the development of potent STS inhibitors for use as anti-cancer agents. There are now several steroidal and non-steroidal STS inhibitors available. New in vivo models, using ovariectomized female nude mice, have been developed to pre-clinically test these inhibitors. These studies have demonstrated the excellent efficacy and effect of STS inhibitors on breast carcinoma development. Recently, 667 COUMATE, an irreversible type of inhibitor which utilizes a phenol sulfamate ester as its active pharmacophore, has completed a Phase I clinical trial in postmenopausal women with breast cancer. These studies have indicated the potential clinical benefit for the use of STS inhibitors. Most pre-clinical and clinical studies have focused on breast cancer as the target for STS inhibition. However, there are other hormone-dependent malignancies, such as endometrial and prostate cancer, that could in the future be treated with these new potent STS inhibitors.     

Thiosemicarbazones of formyl benzoic acids as novel potent inhibitors of estrone sulfatase

Thiosemicarbazones of the microbial metabolite madurahydroxylactone, a polysubstituted benzo[a]naphthacenequinone, have been previously reported by us as potent nonsteroidal inhibitors of the enzyme estrone sulfatase (cyclohexylthiosemicarbazone 1, IC50 0.46 microM). The active pharmacophore of 1 has now been identified to be 2-formyl-6-hydroxybenzoic acid cyclohexylthiosemicarbazone (25, IC50 4.2 microM). The active partial structure was derivatized in the search for novel agents against hormone-dependent breast cancer. Further substantial increases in activity were achieved by reversal of functional groups leading to the cyclohexylthiosemicarbazones of 5-formylsalicylic acid (35, IC50 0.05 microM) and 3-formylsalicylic acid (34, IC50 0.15 microM) as the most potent analogues identified to date. Both compounds were shown to be noncompetitive inhibitors of estrone sulfatase with Ki values of 0.13 microM and 0.12 microM, respectively. The compounds showed low acute toxicity in the hen's fertile egg screening test.     

Ethynyl cleavage of 17 alpha-ethynylestradiol in the rhesus monkey

17 alpha-Ethynylestradiol (EE2)[20,21-14C] and [9,11-3H] were administered by intragastric intubation to three adult female rhesus monkeys. Quantification of the tritium isotope indicated that the peak plasma radioactivity (3.4-6.8% of dose) occurred between 30 and 60 min, whereas 36-39% of the administered tritium appeared in the urine in the first 96 hr. Fecal excretion was 9.17.0% during the same period. Fractionation and isolation of the urinary conjugates were accomplished by chromatography on Sephadex LH-20 followed by HPLC. Cochromatography of radioactive fractions with authentic steroid glucuronide standards gave presumptive evidence for the presence of ethynylestradiol and estrone glucuronides. Following hydrolysis, the tritium-labeled natural estrogens, estrone and estradiol-17 beta, were identified with reverse-isotope recrystallization, demonstrating that the de-ethynylation of EE2 had occurred.     

Synthesis and Biological Evaluation of Fluorinated 3‐Phenylcoumarin‐7‐O‐Sulfamate Derivatives as Steroid Sulfatase Inhibitors

In the present work, we report the initial results of our study on a series of 3‐phenylcoumarin sulfamate‐based compounds containing C‐F bonds as novel inhibitors of steroid sulfatase. The new compounds are potent steroid sulfatase inhibitors, possessing more than 10 times higher inhibitory potency than coumarin‐7‐O‐sulfamate. In the course of our investigation, compounds 2b and 2c demonstrated the highest inhibitory effect on the enzymatic steroid sulfatase assay; both had IC₅₀ values of 0.27 μm (the IC₅₀ value of coumarin‐7‐O‐sulfamate is 3.5 μm , used as a reference).     

Solid-phase organic synthesis (SPOS) of modulators of estrogenic and androgenic action

Estrogens and androgens are key growing factors involved in a large series of disorders. Two main strategies are possible for controlling their undesirable agonist effects: (1) blocking their biosynthesis by using selective enzyme inhibitors, and (2) antagonizing their hormonal action on a receptor with an antiestrogen or an antiandrogen. In this review, we will briefly discuss the identification of a series of important therapeutic targets, through the study of steroidogenesis of potent estrogens, estrone and estradiol, and potent androgens, testosterone and dihydrotestosterone, as well as of their nuclear receptors. We will next review the solid-phase synthesis of steroidogenic enzyme (steroid sulfatase and 17beta-hydroxysteroid dehydrogenases) inhibitors and steroid (estrogen and androgen) receptor modulators, all being potential therapeutic agents for the treatment of hormone-sensitive diseases.     

Stilbene-based inhibitors of estrone sulfatase with a dual mode of action in human breast cancer cells

Estrone sulfate (E1S) is an endogenous prodrug that delivers estrone and, subsequently, estradiol to target cells, after hydrolysis by the enzyme estrone sulfatase, which is active in various tissues including hormone-dependent breast cancer. Blockade of this enzyme should reduce the estrogen level in breast cancer cells and prevent hormonal growth stimulation. In this study, a number of sulfamoyloxy-substituted stilbenes with side chains that guarantee antiestrogenic activity were synthesized and evaluated as inhibitors of estrone sulfatase. They inhibited this enzyme in human MDA-MB 231 breast cancer cells, with IC(50) values in the submicromolar range. The effects of both the free hydroxy derivatives and the sulfamates on gene activation were determined in transfected MCF-7/2a breast cancer cells stimulated either with estradiol or with estrone sulfate. The analysis of data revealed a dual mode of action of the majority of compounds. They blocked gene expression by inhibition of estrone sulfatase and by antiestrogenic action. This pharmacological profile was also observed in assays on antiproliferative activity. The most potent derivative 8 g inhibited the growth of wild-type human MCF-7 cells with an IC(50) value of 13 nM.     

Chloroquine phosphate and the intestinal transport of estrogens

The effect of the antimalaria drug, chloroquine phosphate, on the transport of [³H]estradiol and [³H]estrone sulphate was studied in isolated sacs of rat duodenum. Net transport of the two estrogens from the mucosal to the serosal sides of the intestinal segment was significantly stimulated at chloroquine concentration of 1.0 mM or higher. However, the transformation of estradiol to estrone glucuronide and of estrone sulphate to estrone, which is normally associated with the transport of these estrogens, was significantly inhibited in the presence of the drug.     

Cytotoxic estrogens: anilin mustard linked 1,1,2-triphenylbut-1-enes with mammary tumor inhibiting activity

In order to develop cytotoxic estrogens with a specific effect on hormone-dependent mammary tumors, two 1,1,2-triphenylbut-1-enes with a 4-OH group at one C-1-phenyl ring and a chloro-[4] or bromo-[8] anilin mustard moiety at the other C-1-phenyl ring were synthesized. 4 and 8 exerted strong alkylating activity and an irreversible binding to the estrogen receptor. In spite of relatively low receptor affinities, both anilin mustards exhibited a better effect on a receptor-positive breast cancer cell line as well as on a hormone-dependent mammary carcinoma of the mouse than on a receptor-negative cell line and a hormone-independent mammary carcinoma. Therefore, a selective antitumor activity of 4 and 8 is likely.     

Inhibition of specific opiate binding to synaptic membrane by cerebroside sulfatase.

The role of cerebroside sulfate in the specific binding of opiates to the synaptic membrane was investigated by the use of the enzyme, sulfatase A (cerebroside sulfatase, cerebroside-3-sulfate-3-sulphohydrolyase, EC 3.1.6.8). It was observed that the hydrolysis of sulfatides in the synaptic membrane by this enzyme was dependent on the presence of a heat stable protein molecule. When [³H]naloxone binding to the enzyme-treated membrane was determined, specific binding was attenuated. This inhibition of specific binding was dependent on the concentration of the activator molecule and could not be prevented by the addition of bovine serum albumin in the binding assay mixtures. The enzymatic pH optimum for inhibiting the specific opiate binding was between pH 4.7 and 5.0. This correlated well with the pH optimum for the sulfatase A to hydrolyze free cerebroside sulfate molecules. Scatchard analysis indicated a significant decrease in the number of binding sites with no statistically significant alteration in binding affinity of the remaining sites.     

The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux.

The potential inhibitory effect on P-glycoprotein (Pgp) by antiparasitic drugs and natural compounds was investigated. Compounds were screened for Pgp interaction based on inhibition of Pgp mediated [3H]-taxol transport in Caco-2 cells. Bidirectional transport of selected inhibitors was further evaluated to identify potential Pgp substrates using the Caco-2 cells. Of 21 antiparasitics tested, 14 were found to inhibit Pgp mediated [3H]-taxol with K(iapp) values in the range 4-2000 microM. The antimalarial quinine was the most potent inhibitor with a K(iapp) of 4 microM. Of the 12 natural compounds tested, 3 inhibited [3H]-taxol transport with K(iapp) values in the range 50-400 microM. Quinine, amodiaquine, chloroquine, flavone, genistein, praziquantel, quercetin and thiabendazole were further investigated in bidirectional transport assays to determine whether they were substrates for Pgp. Transport of quinine in the secretory direction exceeded that in the absorptive direction and was saturable, suggesting quinine being a Pgp substrate. The rest of the compounds inhibiting Pgp showed no evidence of being Pgp substrates. In conclusion, we have demonstrated that a substantial number of antiparasitic and natural compounds, in a range of concentrations, are capable of inhibiting Pgp mediated [3H]-taxol efflux in Caco-2 cells, without being substrates and this may have implications for drug interactions with Pgp.     

2-Phenylindoles. Effect of N-benzylation on estrogen receptor affinity, estrogenic properties, and mammary tumor inhibiting activity

Hydroxy-2-phenylindoles carrying substituted benzyl groups and similar substituents at the nitrogen were synthesized and tested for their ability to displace estradiol from its receptor. All of the derivatives tested exhibited high binding affinities for the calf uterine estrogen receptor, with RBA values ranging from 0.55 to 16 (estradiol 100). The mouse uterine weight tested revealed only low estrogenicity for this class of compounds. Several derivatives showed antiestrogenic activity with a maximum inhibition of estrone-stimulated uterine growth of 40%. Two of the compounds (6c, 21c) were tested for antitumor activity in dimethylbenanthracene- (DMBA-) induced estrogen-dependent rat mammary tumors. Only the 4-cyanobenzyl derivative 21c was active. After 4 weeks of treatment with 12 mg/kg (6 times/week), the average tumor area was decreased by 57% (control +204%). In vitro, an inhibitory effect of 21b was only observed with hormone-sensitive MCF-7 breast cancer cells but not with hormone-independent MDA-MB 231 cells. These results make a mode of action involving the estrogen receptor system likely.     

Carbonic anhydrase inhibitors. Inhibition of cytosolic isozymes I and II and transmembrane,tumor-associated isozyme IX with sulfamates including EMATE also acting as steroid sulfatase inhibitors

A series of sulfamates or bis-sulfamates incorporating aliphatic, aromatic, polycyclic (steroidal), and sugar moieties in their molecules has been synthesized and assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more precisely of the cytosolic isozymes CA I andII, and the transmembrane, tumor-associated isozymes CA IX. Some of these compounds were previously reported to act as inhibitors of steroid sulfatases, among which estrone sulfatase (ES) and dehydroepiandrosterone sulfatase (DHEAS) are the key therapeutic targets for estrogen-dependent tumors. Very potent (nanomolar) inhibitors were detected against the three investigated CA isozymes. Best CA I inhibitors were phenylsulfamate and some of its 4-halogeno derivatives, as well as the aliphatic compound n-octyl sulfamate. Against CA II, low nanomolar inhibitors (1.1-5 nM) were phenylsulfamate and some of its 4-halogeno/nitro derivatives, n-octyl sulfamate, and estradiol 3,17beta-disulfamate among others. All the investigated sulfamates showed efficient CA IX inhibitory properties, with inhibition constants in the range of 18-63 nM. The best CA IX inhibitor detected so far was 4-chlorophenylsulfamate. These data are critical for the design of novel antitumor properties, mainly for hypoxic tumors that overexpress CA IX, which are nonresponsive to radiation or chemotherapy. The antitumor properties of the ES/DHEAS inhibitors in clinical trials may on the other hand also be due to their potent inhibitory properties of CA isozymes involved in tumorigenicity, such as CA II and CA IX.     

2-Phenylindole-linked [2-(aminoalkyl)pyridine]dichloroplatinum(II): complexes with a selective action on estrogen receptor positive mammary tumors

A number of [2-(aminomethyl)pyridine]dichloroplatinum(II) complexes, linked to 5-hydroxy-2-(4-hydroxyphenyl)indoles by alkyl spacer groups of varying lengths, were synthesized and studied for their binding affinities for the calf uterine estrogen receptor. Their relative binding affinity (RBA) values ranged from 1.0 to 5.2% (estradiol, RBA = 100%). Highest affinities were found with complexes possessing a (CH2)5- or (CH2)6-bridge between the pyridine aminomethyl group and the indole nitrogen. Endocrine activities of the complexes and their ligands, determined in the mouse uterine weight test, were low. All compounds entered comparative tests using estrogen receptor positive and negative mammary tumor models. In cell culture, a growth inhibiting effect was only observed in hormone-sensitive MCF-7 cells, but not in hormone-independent MDA-MB 231 cells. In this assay, there was no significant difference between complexes and their ligands. In vivo, the growth of estrogen receptor positive MXT mouse mammary tumors was strongly inhibited by the complexes whereas the hormone-independent MXT mammary tumors showed only a minor response. At a dose of 3 X 20 mg/kg per week, complexes 10d-g reduced the tumor weight by ca. 80% after 6 weeks of treatment. This effect was generally stronger than that exerted by the ligands. The doses applied were well tolerated. Since the complexes described in this paper require the estrogen receptor for their action, a mechanism similar to that of antiestrogens is assumed.     

Confocal fluorescence detection expanded to UV excitation: the first continuous fluorimetric assay of human steroid sulfatase in nanoliter volume

Steroid sulfatase is an enzyme that currently enjoys considerable interest as a potential drug target in the treatment of estrogen- and androgen-dependent diseases, in particular breast cancer. We have purified human steroid sulfatase to apparent homogeneity from recombinant Chinese hamster ovary cells, and we established an assay with a new fluorogenic substrate, 3,4-benzocoumarin-7-O-sulfate (1). Substrate 1 features a K(m) value of 22.5 microM, which is close to the value for the natural substrate dehydroepiandrosterone sulfate (26 microM) and much lower than the K(m) values of other synthetic substrates (276-736 microM). Importantly, the cleavage of substrate 1 can be monitored continuously during the enzymatic cleavage, since a change in fluorescence intensity is detectable at the pH where the enzyme is active; in contrast, all other synthetic substrates described so far require alkalization to reveal a measurable absorbance or fluorescence signal. The adaptation of the assay to the 96-well format allows continuous monitoring of multiple wells in a microplate fluorescence reader. Applications of the assay for the determination of IC(50) and K(i) values of novel steroid sulfatase inhibitors are presented. Most importantly the assay was transferred to the nanoscale format (1-microl assay volume) in 2080-well plates with confocal fluorescence detection. This miniaturization will permit screening with a minimum throughput of 20000 compounds per day. The system presented demonstrates that the confocal detection platform used for nanoscreening can be successfully adapted to assays for which conventional ultraviolet dyes like coumarins are necessary. This strongly broadens the application range of confocal readers in drug screening.     

Bacterial Lipopolysaccharides Induce Steroid Sulfatase Expression and Cell Migration through IL-6 Pathway in Human Prostate Cancer Cells

Steroid sulfatase (STS) is responsiblefor the conversion of estrone sulfate to estrone that can stimulate growth in endocrine-dependent tumors such as prostate cancer. Although STS is considered as a therapeutic target for the estrogen-dependent diseases, cellular function of STS are still not clear. Previously, we found that tumor necrosis factor (TNF)-α significantly enhances steroid sulfatase expression in PC-3 human prostate cancer cells through PI3K/Akt-dependent pathways. Here, we studied whether bacterial lipopolysaccharides (LPS) which are known to induce TNF-α may increase STS expression. Treatment with LPS in PC-3 cells induced STS mRNA and protein in concentration- and time-dependent manners. Using luciferase reporter assay, we found that LPS enhanced STS promoter activity. Moreover, STS expression induced by LPS increased PC-3 tumor cell migration determined by wound healing assay. We investigated that LPS induced IL-6 expression and IL-6 increased STS expression. Taken together, these data strongly suggest that LPS induces STS expression through IL-6 pathway in human prostate cancer cells.