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CELLULAR METABOLISM
1Osaka Prefecture University, Graduate School of Veterinary Medicine, Department of Toxicology, Sakai, Osaka, Japan; and 2Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
Submitted 14 July 2005 ; accepted in final form 5 February 2006
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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-estradiol had no effect on activation of matriptase in hormone-starved breast cancer cells, in part due to their high constitutive level of activated matriptase. In striking contrast, very low levels of activated matriptase were detected in hormone-starved lymph node prostatic adenocarcinoma (LNCaP) cells. Robust activation of matriptase was observed as early as 6 h after exposure of these cells to 5
-dihydrotestosterone (DHT). Activation of matriptase was closely followed by shedding of the activated matriptase with >90% of total activated matriptase present in the culture media 24 h after DHT treatment. Activated matriptase was shed in a complex with HAI-1 and may result from simultaneously proteolytic cleavages of both membrane-bound proteins. Latent matriptase and free HAI-1 were also shed into culture media. As a result of shedding, the cellular levels of matriptase and HAI-1 were significantly reduced 24 h after exposure to DHT. DHT-induced matriptase activation and shedding were significantly inhibited by the androgen antagonist bicalutamide, by the RNA transcription inhibitor actinomycin D, and by the protein synthesis inhibitor cycloheximide. These results suggest that in LNCaP cells, androgen induces matriptase activation via the androgen receptor, and requires transcription and protein synthesis. androgen; hepatocyte growth factor activator inhibitor-1
The role of matriptase in tumor onset and progression goes beyond its deregulated expression and imbalance to HAI-1 in human cancers. For example, the stability and proteolytic activity of matriptase can be enhanced by modification of its glycosylation status by 1,6-N-acetylglucosaminyltransferase V, a prometastatic enzyme (15, 16). Its deregulation in breast cancer cells also occurs at the level of activation. In mammary epithelial cells, matriptase activation depends on the presence of sphingosine 1-phosphate (S1P), a blood-borne lysophospholipid (2, 3); breast cancer cells, however, constitutively activate matriptase regardless of the presence of S1P (4). The balance of matriptase and HAI-1 levels also affects the activation of matriptase, and reduced expression of HAI-1 by small interfering RNA results in spontaneous activation of matriptase and enhanced S1P-induced matriptase activation in human mammary epithelial cells (43). Recently, both matriptase and HAI-1 were identified by quantitative proteomic analysis as cellular proteins shed into culture media in response to androgen exposure in LNCaP prostate cancer cells, along with the canonical androgen responsive protease, prostate-specific antigen (PSA) (35). Because ectodomain shedding of matriptase and HAI-1 closely follow the activation of matriptase (2), androgen exposure might also cause activation of matriptase in prostate cancer cells. Therefore, we proposed that matriptase activation might be regulated by steroid sex hormones and so we initiated the current study to investigate matriptase activation in response to steroid sex hormones, in both prostate and breast cancer cells.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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-Dihydrotestosterone (DHT), 17-estradiol (E2), and 4-hydroxytamoxifen (OHT) were obtained from Sigma (St. Louis, MO). Actinomycin D and cycloheximide were obtained from Biomol (Plymouth Meeting, PA). Bicalutamide was obtained from Toronto Research Chemicals (North York, ON, Canada). All other chemical reagents were obtained from Sigma unless otherwise specified. Cell culture conditions. Human cancer cells were obtained from the Tissue Culture Shared Resource of the Lombardi Comprehensive Cancer Center, Georgetown University Medical Center. The breast cancer cells (T-47D, MCF-7, and MDA MB-468) were maintained in culture by growth in Iscove's minimal essential media (IMEM; Invitrogen, Rockville, MD) supplemented with 5% fetal bovine serum (FBS), 100 U/ml penicillin, and 100 µg/ml streptomycin in a humidified chamber at 37°C and 5% CO2. LNCaP, PC-3, and DU145 human prostate cancer cells were routinely maintained in RPMI 1640 supplemented with 5% FBS, 1% glutamine, and 0.5% gentamicin in a humidified chamber at 37°C and 5% CO2 (41).
To investigate the effects of estrogen on breast cancer cells, T-47D (2 x 103/cm2), MCF-7 (5 x 103/cm2), and MDA MB-468 (3 x 103/cm2) were cultured for 2 days, washed once with phosphate-buffered saline (PBS), and subjected to serum and hormone starvation in steroid-reduced IMEM [10 mM HEPES-buffered (pH 7.2) phenol red-free IMEM, containing 100 U/ml penicillin and 100 µg/ml streptomycin], containing 5% charcoal/dextran-treated FBS (Hyclone, Logan, UT), and 1 µM OHT for a day, followed by steroid-reduced IMEM containing 1% charcoal/dextran-treated FBS and 0.2 µM OHT for an additional day. The cultures were then washed twice with PBS and treated with OHT or E2 in a steroid-reduced IMEM for 24 h. To investigate androgen effects on prostate cancer cells, LNCaP (3 x 104/cm2), PC-3 (5 x 103/cm2) and DU145 (5 x 103/cm2) were cultured 2 days, washed once with PBS, and then subjected to serum and hormone starvation in a steroid-reduced RPMI 1640 [10 mM HEPES-buffered (pH 7.2), phenol red-free RPMI 1640, containing 1% glutamine and 0.5% gentamicin], containing 5% charcoal/dextran-treated FBS for a day, followed by culture in steroid-reduced RPMI containing 1% charcoal/dextran-treated FBS for an additional day. The cultures were then washed once with PBS and treated with DHT in a steroid-reduced RPMI for the indicated period.
Cell viability assay. Because cycloheximide and actinomycin D are known to be somewhat toxic, the viability of LNCaP cells after cycloheximide or actinomycin D treatment was monitored by Trypan blue exclusion. Those treated cells were trypsinized, collected, and stained with Trypan blue solution according to the commercial protocol. Under a microscope, live and dead cells were counted in a hemocytometer. The majority of cells (from 90% to 80%) were viable after these treatments.
Monoclonal antibodies. Human matriptase protein was detected using either the M32 monoclonal antibody, which recognizes the third LDL receptor class A domain of matriptase of both the latent (one chain) and activated (two chain) forms of the protease, or using the M69 monoclonal antibody, which recognizes an epitope present only in the activated (two chain) form of the enzyme (2, 3). Human HAI-1 was detected using the HAI-1 specific monoclonal antibody M19 (29). Characterization of mAbs used in the current study, including M69, M32, and M19 is summarized in Table 1.
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RNA preparation and analysis. Cells for RNA studies were cultured and treated with steroids as described. Total RNA was prepared using Tri Reagent (Sigma), following the manufacturer’s instructions, and RNA quality and concentration was determined by absorbance measurements and electrophoretic analysis on denaturing agarose gels. Matriptase and PSA mRNA levels were measured by real-time RT-PCR using standard methods. Briefly, aliquots of total RNA were treated with RQ1 RNase-free DNase (Promega) to remove any contaminating genomic DNA and then used to generate cDNA using the avian myoblastosis virus-reverse transcriptase system (Promega) per the manufacturer's instructions. The resultant cDNA was subjected to real-time singleplex PCR using Assays-on-Demand gene expression products [20x mix of unlabeled PCR primers and hexachloro-6-carboxy-fluorescine (FAM) or VIC dye-labeled TaqMan MGB probe] specific for matriptase, PSA, or GAPDH (AB Applied Biosystems) according to manufacturer's instructions. The relative standard curve method was used to quantitate the expression levels of each gene. GAPDH was used as the endogenous reference to normalize samples and results are expressed relative to the level in control cells. The means ± SD of triplicate determinations are presented.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Low levels of activated matriptase were detected in all three hormone-starved prostate cancer cell lines, either in cell lysates or in conditioned media. In contrast to PC-3 and DU145 cells, which showed no obvious response to androgen with regard to matriptase activation (data not shown), in the androgen-sensitive LNCaP cells, DHT induced matriptase activation in a dose-dependent manner (Fig. 1A; M69). The levels of activated matriptase, both in the cell lysate and in the conditioned media, were significantly increased by the treatment with 10–9 M DHT, compared with those of untreated cells (Fig. 1A). While there was no obvious difference in the cellular levels of activated matriptase, comparing 10–9 M DHT to 10–8 M DHT (Fig. 1A, M69 cell lysate), treatment with 10–8 M DHT resulted in the presence of much more activated matriptase in the conditioned media (Fig. 1A, M69 medium). These data suggest that matriptase activation in LNCaP prostate cancer cells is regulated by androgen, and that the majority of activated matriptase is shed to the extracellular milieu, resulting in relatively constant levels of activated matriptase present in the cells themselves.
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DHT also caused shedding of HAI-1 in a dose-dependent manner (Fig. 1, M19 medium), again at the cost of cellular levels of the inhibitor (Fig. 1A, M19 cell lysate). We detected HAI-1 using mAb M19, which recognizes full-length inhibitor at 55-kDa in cell lysates, and 50- and 40-kDa shed fragments in the conditioned media (Table 1). This mAb also recognizes matriptase-HAI-1 complexes, either in cell lysates at 120 and/or 85 kDa, or in conditioned media at 95 and/or 110 kDa (Table 1) (23, 29). Because the ratio of 120- and 85-kDa complexes, relative to the free form of HAI-1, is sometimes very low, both complexes may not be seen in cell lysate using this mAb.
After hormone starvation, in contrast to prostate cancer cells, breast cancer cells, including T-47D, MCF-7, and MDA MB-468 cells, maintained high levels of activated matriptase, both in cell lysates and conditioned media. Treatment with E2 (0.1 to 10 nM) or 1 µM OHT resulted in no obvious change in the levels of activated matriptase nor the total matriptase and HAI-1 (data not shown). While some breast cancer cells (T-47D, MCF-7, and MDA MB-453) also express androgen receptor (8), there was no obvious change in the levels of matriptase activation in these breast cancer cells after exposure of DHT (data not shown). This may be due to the high levels of activated matriptase in hormone-starved breast cancer cells. Interestingly, E2 (10 nM) can induce matriptase activation and shedding in LNCaP prostate cancer cells (data not shown). This is probably because these cells express a mutated form of the androgen receptor that is known to bind estradiol (60).
Kinetics of DHT effects on matriptase activation and ectodomain shedding of matriptase and HAI-1 in LNCaP prostate cancer cells. We determined the time course of the DHT effect on matriptase activation, and the temporal relationship of matriptase activation and ectodomain shedding of the protease and the inhibitor (Fig. 2). Activated matriptase appeared in LNCaP cell lysates 6 h after DHT treatment, accumulated to the highest level at 18 h, and decreased at 24 h (Fig. 2; M69 cell lysate). Consistent with the appearance of activated matriptase in cell lysates 6 h after DHT treatment, activated matriptase also began to appear in culture media, whereas at very low levels, 6 h after DHT treatment (Fig. 2, M69 medium). Continuous accumulation of activated matriptase was observed, reaching very high levels 24 h after DHT treatment (Fig. 2, M69 medium). The cellular levels of 70-kDa, latent matriptase, were similar in control and DHT-treated cells, up to 3 h after DHT treatment (Fig. 2, M32 Cell lysate). However, after 6 h of DHT treatment, when the activation began to occur, the cellular levels of latent matriptase began to decrease, and were maintained at low levels for up to 24 h after treatment (Fig. 2, M32 cell lysate). This long-term decrease in matriptase levels was consistent with the conversion of latent-to-activated matriptase and shedding of the protease to culture media. Accompanying the decrease in cellular levels of matriptase during its activation, 70-kDa latent matriptase accumulated to very high levels 12 h after DHT treatment (Fig. 2, M32 medium). Similar to the protease, cellular levels of HAI-1 were stable before matriptase activation, and decreased during activation of matriptase (Fig. 2, M19 cell lysate). Shedding of HAI-1 appeared to be more complex than matriptase. After stimulation of DHT-starved cells, shedding of the 50-kDa HAI-1 fragment was detected for only 3 h, and the 40-kDa fragment was detected after 12 h (Fig. 2, M19 medium). DHT treatment did not increase the shedding of the 50-kDa HAI-1 fragment, but significantly boosted the levels of the 40-kDa HAI-1 fragment in culture media. The shedding of HAI-1 in its 95-kDa complex, which contains activated matriptase and 40-kDa HAI-1 fragment, totally depended on the presence of DHT and followed the same pattern as activated matriptase (Fig. 2, M19 medium). While DHT-induced shedding of HAI-1 did cause a decrease in its cellular levels, the constitutive shedding of the 50-kDa HAI-1 fragment in the absence of DHT did not result in reduced cellular levels of HAI-1 (Fig. 2, M19 cell lysate). This could represent a balance between biosynthesis and shedding in the absence of androgen. Treatment of cells with androgen apparently potentiated shedding but did not increase the biosynthesis of HAI-1 enough to maintain cellular levels of the inhibitor. These data also suggest that there may be two different proteases responsible for the shedding of HAI-1: one protease that converts the 55-kDa, membrane-bound, full-length HAI-1 to a 50-kDa fragment, and another to convert the 55-kDa HAI-1 to the 40-kDa fragment. The former could occur constitutively, the latter being enhanced by androgen exposure and/or by activation of matriptase.
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Androgen receptor is involved in DHT-induced activation and shedding of matriptase. We examined the molecular mechanisms involved in androgen-induced matriptase activation and its subsequent shedding. Cellular responses to androgen are mainly mediated via the activation of the intracellular androgen receptor (AR) (21, 25, 63) or the putative cell surface receptor, likely to be a G protein-coupled receptor (5). Thus we investigated whether AR is involved in DHT-induced matriptase activation and shedding by using the AR antagonist, bicalutamide (6, 37), and by using albumin-conjugated testosterone, which cannot penetrate through the plasma membrane to activate the intracellular AR (27). While bicalutamide did not alter cellular levels of DHT-induced activated matriptase (Fig. 3A, M69 cell lysate), the AR antagonist significantly reduced the levels of DHT-induced activated matriptase in the conditioned media (Fig. 3A, M69 medium). Because the shed, activated matriptase represents >90% of the total activated matriptase, these data clearly suggest that bicalutamide significantly inhibits DHT-induced matriptase activation and that AR is involved in mediating the effect of DHT on matriptase activation. Accordingly, the cellular level of latent matriptase was much higher (Fig. 3A, M32 cell lysate) and the shed latent matriptase was lower (Fig. 3A, M32 medium) in bicalutamide-pretreated cells, compared with cells treated with DHT alone. HAI-1 shared a similar trend but less obvious trend (Fig. 3A, M19). The inhibition of DHT-induced PSA expression by bicalutamide was included as an experimental control (Fig. 3A, PSA). In a manner consistent with the selective involvement of intracellular AR in activation of matriptase, BSA-testosterone at 100 nM failed to induce matriptase activation and shedding (Fig. 3B).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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After matriptase activation, inhibition of active matriptase appeared to occur immediately via the binding of active matriptase with its cognate inhibitor HAI-1, since all activated matriptase, both in the cell and in conditioned media, was detected in HAI-1 complexes. This rapid and efficient inhibition of matriptase by HAI-1 could result from the required participation of HAI-1 in matriptase activation (46) and the presence of HAI-1 with matriptase in activation foci (23). This mode of inhibition of matriptase by HAI-1 in prostate cancer cells seems to be identical to that observed in mammary epithelial cells, in which activation of matriptase can be induced by S1P and suramin. The shedding of matriptase-HAI-1 complexes occurred as early as 6 h after the cellular treatment with DHT and temporally correlated with the onset of matriptase activation (Fig. 2). Because proteolytic cleavages of both matriptase and HAI-1 are required for the removal of the matriptase-HAI-1 complex from cell surfaces, a well-coordinated mechanism, probably involving other proteases, could be turned on right after activation and inhibition of matriptase. This cellular clearance of activated matriptase could provide a final mechanism to remove active matriptase, a potentially biohazardous molecule.
Whereas all of these well-coordinated events are triggered by androgen, the questions of how and when matriptase acts on its substrates are a major missing link in our understanding of matriptase functionality and regulation. Because the half-life of active matriptase is likely to be very short, it is plausible that the physiological substrates of matriptase (as yet largely unknown) could also be present where matriptase activation occurs, and conceivably, these substrates may even participate in matriptase activation. Because of the close association between matriptase activation and its shedding with HAI-1, a process which also requires proteolytic cleavage at both HAI-1 and matriptase, we propose that some of the matriptase substrates may be other membrane-bound proteases and could be involved in the shedding of matriptase and HAI-1. Thus matriptase may activate the protease(s) responsible for its own shedding; removal of activated matriptase from cell surfaces may be closely coupled to the activation of matriptase.
Two matriptase-HAI-1 complexes of 110 and 95 kDa were detected in the conditioned media of breast cancer cells. Both the 110- and 95-kDa complexes contain 70-kDa matriptase. Their size differences reside in the sizes of HAI-1 fragments. The 110-kDa complex contains the 50-kDa HAI-1 fragment and the 95-kDa complex contains the 40-kDa HAI-1 fragment. How are these two HAI-1 fragments generated and are they the products of one protease or two different proteases? This study of LNCaP cells provides some clues to this question. Despite constitutive shedding of the 50-kDa HAI-1 fragment, LNCaP prostate cancer cells shed the 95-kDa complex and the 40-kDa HAI-1 fragment, but not the 110-kDa complex in response to androgen treatment. These data suggest that LNCaP cells may express two different proteases responsible for the shedding of HAI-1: one protease being constitutively active and responsible for the shedding of the 50-kDa HAI-1 fragment and another protease that becomes active only in response to androgen treatment and cleaves HAI-1 at a different site resulting in the shedding of the 40-kDa HAI-1 fragment and the 95-kDa matriptase-HAI-complex.
The impact of matriptase activation on LNCaP prostate cancer cell biology may lie in the substrates, which are directly or indirectly activated by matriptase. Previously, three substrates of matriptase were identified in an in vitro setting, including urokinase-type plasminogen activator, HGF/scatter factor, and protease-activated receptor-2 (PAR-2) (20, 24, 53, 56). To our knowledge, neither the urokinase-type plasminogen activator nor HGF is expressed by LNCaP cells. Therefore, the role of matriptase in cancer invasion and metastasis via urokinase and HGF may require interaction with stromal cells in vivo in some prostate cancers. Interestingly, the G protein-coupled receptor PAR-2 is expressed by LNCaP cells and participates in the activation of the small GTPase RhoA and subsequent actin filament rearrangement (12). It is of interest for future studies to determine whether DHT can cause activation of PAR-2 via the activation of matriptase.
Besides matriptase and PSA, several proteases, including human gland kallikrein (62), a protease with high homology with enamel matrix serine proteinase 1 (39), protease/KLK-L1 (64), TMPRSS2 (1, 28), and MMP-2 (26), are regulated by androgen in prostate cells. Matriptase is unique among these androgen-regulated proteases in that its regulation by androgen occurs mainly at the level of activation. While androgen can enhance the activation of these other androgen-regulated proteases (1), the increased protease activation mainly results from its increased expression. The tight coupling of matriptase shedding with its activation also distinguishes matriptase from the other androgen-regulated proteases. While both matriptase and PSA are released into the extracellular milieu in response to androgen exposure, the mechanisms by which androgens induce their release are very different. In contrast to PSA, whose expression and secretion were induced by androgen, prostate cancer cells constitutively express matriptase and HAI-1. Androgen clearly works to selectively induce ectodomain shedding of matriptase and HAI-1, as a consequence of androgen-induced activation of matriptase. While both matriptase and HAI-1 were shed either in free form or complexed forms in cultured cells, we have previously detected only the complexed form of the enzyme in human milk (29). These observations suggest that under physiological conditions such as lactation, ectodomain shedding occurs only for the matriptase-HAI-1 complex, and not for latent matriptase and free HAI-1. It remains to be determined whether shedding of latent matriptase and free HAI-1 fragments are associated with cell culture conditions or with the malignant progression.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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