[Show abstract][Hide abstract] ABSTRACT: Lung cancer is the leading cause of cancer death worldwide. There is an urgent need for early diagnostic tools and novel therapies in order to increase lung cancer survival. Secretory phospholipase A2 group IIa (sPLA2-IIa) is involved in inflammation, tumorigenesis and metastasis. We were the first to uncover that cancer cells secrete sPLA2‑IIa. sPLA2‑IIa is overexpressed in almost all specimens of human lung cancers examined and is significantly elevated in the plasma of lung cancer patients. High levels of plasma sPLA2-IIa are significantly associated with advanced stage and decreased overall cancer survival. In this study, we further showed that elevated HER/HER2‑PI3K-Akt-NF-κB signaling contributes to sPLA2-IIa overexpression in lung cancer cells. sPLA2-IIa in turn phosphorylates and activates HER2 and HER3 in a time- and dose‑dependent manner in lung cancer cells. The structure and sequence‑based docking analysis revealed that sPLA2-IIa β hairpin shares structural similarity with the corresponding EGF hairpin. sPLA2-IIa forms an extensive interface with EGFR and brings the two lobes of EGFR into an active conformation. sPLA2-IIa also enhances the NF-κB promoter activity. Anti-sPLA2-IIa antibody, but not the small molecule sPLA2-IIa inhibitor LY315920, significantly inhibits sPLA2‑IIa-induced activation of NF-κB promoter. Our findings support the notion that sPLA2-IIa functions as a ligand for the EGFR family of receptors leading to an elevated HER/HER2-elicited signaling. Plasma sPLA2-IIa can potentially serve as lung cancer biomarker and sPLA2‑IIa is a potential therapeutic target against lung cancer.
[Show abstract][Hide abstract] ABSTRACT: Mg-4 wt.% Zn-0.5 wt.% Zr (ZK40) alloy was studied as a candidate material for biodegradable metallic implants in terms of its biocorrosion resistance, mechanical properties and cytocompatibility using Dulbecco's modified Eagle's medium (DMEM). The corrosion characteristics of ZK40 alloy were assessed by potentiodynamic polarization and immersion testing in DMEM + 10% FBS solution. Analysis of the degradation characteristics by potentiodynamic polarization measurements shows the corrosion rates of ZK40 were reduced after solution treatment (T4) and these rates were observed to be slightly higher than those of pure Mg or as-drawn AZ31. Determination of the corrosion rate by the weight loss technique reveals that as-cast ZK40 resulted in slower degradation than other alloy specimens after 7 days of immersion but exhibited accelerated degradation after 14 and 21 days. T4-treated ZK40 exhibited stable degradation rates compared to as-cast ZK40 and close to those of pure Mg and AZ31 during immersion testing for 14 and 21 days. In order to examine the in vitro cytocompatibility of ZK40 alloy, live/dead cell viability assay and indirect MTT assay were performed using a murine osteoblast-like cell line (MC3T3). After 3 days of direct culture of MC3T3 on ZK40 alloys the live/dead assay indicated favorable cell viability and attachment. The presence of fixed MC3T3 cells after the live/dead assay showed the cells were able to proliferate on the surface. The degradation product of ZK40 also showed minimal cytotoxicity in indirect MTT assay. The mechanical properties of as-cast and T4-treated ZK40 were observed to be superior to those of pure Mg and comparable to as-drawn AZ31. Solution treatment did not significantly enhance the cytocompatibility and mechanical properties of ZK40 alloy. Overall, the ZK40 alloy exhibited favorable cytocompatibility as well as biocorrosion and mechanical properties comparable to those of AZ31, making it a potential candidate for degradable implant applications.
[Show abstract][Hide abstract] ABSTRACT: This study introduces a class of biodegradable Mg-Y-Ca-Zr alloys novel to biological applications and presents evaluations of the biomaterial for orthopedic and craniofacial implant applications. Mg-Y-Ca-Zr alloys were synthesized using conventional melting and casting techniques. The effects of increasing Y content from 1 wt.% to 4 wt.% and the effects of performing T4 solution treatment were assessed. Basic material phase characterization was conducted using X-ray diffraction, optical microscopy, and scanning electron microscopy. Compressive and tensile tests allowed for the comparison of mechanical properties of the as-cast and T4 treated Mg-Y-Ca-Zr alloys to pure Mg and as-drawn AZ31. Potentiodynamic polarization tests and mass loss immersion tests were used to evaluate the corrosion behavior of the alloys. In vitro cytocompatibility tests on MC3T3-E1 pre-osteoblast cells were also conducted. Finally, alloy pellets were implanted into murine subcutaneous tissue to observe in vivo corrosion as well as local host-response through H&E staining. Secondary phase intermetallics rich in yttrium were observed, with the T4 solution treatment diffusing the secondary phases into the matrix while increasing grain size. The alloys demonstrated marked improvement in mechanical properties over pure Mg. Increasing the Y content contributed to improved corrosion resistance, while solution treated alloys resulted in lower strength and compressive strain compared to as-cast alloys. The Mg-Y-Ca-Zr alloys demonstrated excellent in vitro cytocompatibility and normal in vivo host response. The mechanical, corrosion, and biological evaluations performed in this study demonstrated that Mg-Y-Ca-Zr alloys, especially with higher 4 wt.% Y content, would perform well as orthopedic and craniofacial implant biomaterials.
[Show abstract][Hide abstract] ABSTRACT: Magnesium (Mg) and its alloys have numerous potential applications as biodegradable implants, but the fast degradation rate of Mg alloys at the initial implanted stage could be a problem. This paper describes the modification of the water-based bis-[triethoxysilyl] ethane (BTSE) silane applied to the surface of magnesium–yttrium (Mg–4Y) to increase its corrosion resistance. Surface characterization by SEM, FTIR, and EDX showed that the hydrolysis and condensation of the silane resulted in a covalent bonding to the Mg–4Y surface. Corrosion behavior of the uncoated and coated Mg–4Y alloy was evaluated in different environments by using a novel self-developed corrosion probe. Based on the electrochemical results of DC polarization and electrochemical impedance spectroscopy (EIS), we conclude that the epoxy-modified BTSE silane coating successfully increases the corrosion resistance at the initial stage of implantation. The corrosion rates in the flesh of dead mice environments such as body cavity and subcutaneous tissue of the mice were lower than the corrosion rates in in vitro environments.
Materials Science and Engineering: C. 07/2012; 32(5):1230–1236.
[Show abstract][Hide abstract] ABSTRACT: Proliferating cell nuclear antigen (PCNA), a potential anticancer target, forms a homotrimer and is required for DNA replication and numerous other cellular processes. The purpose of this study was to identify novel small molecules that modulate PCNA activity to affect tumor cell proliferation. An in silico screen of a compound library against a crystal structure of PCNA and a subsequent structural similarity search of the ZINC chemical database were carried out to derive relevant docking partners. Nine compounds, termed PCNA inhibitors (PCNA-Is), were selected for further characterization. PCNA-I1 selectively bound to PCNA trimers with a dissociation constant (K(d)) of ~0.2 to 0.4 μM. PCNA-Is promoted the formation of SDS-refractory PCNA trimers. PCNA-I1 dose- and time-dependently reduced the chromatin-associated PCNA in cells. Consistent with its effects on PCNA trimer stabilization, PCNA-I1 inhibited the growth of tumor cells of various tissue types with an IC(50) of ~0.2 μM, whereas it affected the growth of nontransformed cells at significantly higher concentrations (IC(50), ~1.6 μM). Moreover, uptake of BrdU was dose-dependently reduced in cells treated with PCNA-I1. Mechanistically the PCNA-Is mimicked the effect of PCNA knockdown by siRNA, inducing cancer cell arrest at both the S and G(2)/M phases. Thus, we have identified a class of compounds that can directly bind to PCNA, stabilize PCNA trimers, reduce PCNA association with chromatin, and inhibit tumor cell growth by inducing a cell cycle arrest. They are valuable tools in studying PCNA function and may be useful for future PCNA-targeted cancer therapy.
[Show abstract][Hide abstract] ABSTRACT: The corrosion behavior of pure Mg, AZ31, and AZ91D were evaluated in various in vitro and in vivo environments to investigate the potential application of these metals as biodegradable implant materials. DC polarization tests and immersion tests were performed in different simulated body solutions, such as distilled (DI) water, simulated body fluid (SBF) and phosphate buffered solution (PBS). Mg/Mg alloys were also implanted in different places in a mouse for in vivo weight loss and biocompatibility investigations. The in vivo subcutis bio-corrosion rate was lower than the corrosion rate for all of the in vitro simulated corrosive environments. The Mg/Mg alloys were biocompatible based on histology results for the liver, heart, kidney, skin and lung of the mouse during the two months implantation. Optical microscopy and scanning electron microscopy were carried out to investigate the morphology and topography of Mg/Mg alloys after immersion testing and implantation to understand the corrosion mechanisms.
Journal of Materials Science & Technology. 03/2012; 28(3):261–267.
[Show abstract][Hide abstract] ABSTRACT: Cytochrome P450 1B1 (CYP1B1) is a key P450 enzyme involved in the metabolism of exogenous and endogenous substrates in endocrine-mediated tumors such as prostate cancer. The potential significance of nonsynonymous SNP Leu432Val (rs1056836) as a risk factor in prostate cancer has been extensively studied. The objective of this meta-analysis was to quantitatively summarize the association between CYP1B1 Leu432Val polymorphism and prostate cancer. All eligible studies were searched and acquired from the PubMed and ISI databases. Statistical analysis was performed by using the software STATA 11.0. Ten case-controlled studies from nine eligible publications were identified, which includes 6,668 subjects with 3,221 cases and 3,447 controls. Overall, no significant association was found between the CYP1B1 Leu432Val polymorphism and prostate cancer susceptibility for Val/Val vs Leu/Leu (OR = 1.07; 95% CI: 0.79-1.44; P = 0.67), Leu/Val vs Leu/Leu (OR = 1.05; 95% CI: 0.94-1.17; P = 0.42), Leu/Val + Val/Val vs Leu/Leu (OR = 1.07; 95% CI: 0.91-1.26; P = 0.40) and Val/Val vs Leu/Val + Leu/Leu (OR = 1.11; 95% CI: 0.86-1.44; P = 0.43). However, a higher risk was found among Asians in all genetic models (Val/Val vs Leu/Leu :OR = 2.48, 95% CI: 1.14-5.39, P = 0.02; Leu/Val vs Leu/Leu: OR = 1.40, 95% CI: 1.03-1.89, P = 0.03; Leu/Val + Val/Val vs Leu/Leu: OR = 1.51, 95% CI = 1.14-2.01, P = 0.004; Val/Val vs Leu/Val + Leu/Leu: OR = 2.50, 95% CI = 1.35-4.56, P = 0.004). We were not able to detect any association in the subgroup analysis by source of controls and genotyping method in all genetic models. In conclusion, this meta-analysis provides evidence that CYP1B1 Leu432Val polymorphism is not associated with prostate cancer risk overall with the exception in Asians.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to determine therapeutic effects and systemic toxicity of 212Pb-trastuzumab in an orthotopic model of human prostate cancer cells in nude mice. TCMC-Trastuzumab was radiolabeled with 212Pb. The 212Pb-trastuzumab generated from the procedure was intact and had high binding affinity with a dissociation constant (of 3.9±0.99 nM. PC-3MM2 cells, which expressed a lower level of HER2 both in culture and in tumors, were used in therapy studies. A single intravenous injection of 212Pb-trastuzumab reduced tumor growth by 60-80%, reduced aortic lymph node metastasis, and prolonged the survival of tumor-bearing mice. Treatment with 212Pb-trastuzumab did not cause significant changes in body weight, serum glutamic pyruvic transaminase (SGPT), blood urea nitrogen (BUN), hematological profiles, and histological morphology of several major organs of tumor-bearing mice. These findings suggest that a systemic delivery of 212Pb-trastuzumab could be an effective modality for management of advanced human prostate cancer.
International Journal of Oncology 02/2012; 40(6):1881-8. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Five-year survival for lung cancer has remained at 16% over last several decades largely due to the fact that over 50% of patients are diagnosed with locally-advanced or metastatic disease. Diagnosis at an earlier and potentially curable stage is crucial. Solitary pulmonary nodules (SPNs) are common, but the difficulty lies in the determination of which SPN is malignant. Currently, there is no convenient and reliable biomarker effective for early diagnosis. Secretory phospholipase A2-IIa (sPLA2-IIa) is secreted into the circulation by cancer cells and may allow for an early detection of lung cancer.
Plasma samples from healthy donors, patients with only benign SPN, and patients with lung cancer were analyzed. Expression of sPLA2-IIa protein in lung cancer tissues was also determined.
We found that the levels of plasma sPLA2-IIa were significantly elevated in lung cancer patients. The receiver operating characteristic curve analysis, comparing lung cancer patients to patients with benign nodules, revealed an optimum cutoff value for plasma sPLA2-IIa of 2.4 ng/ml to predict an early stage cancer with 48% sensitivity and 86% specificity and up to 67% sensitivity for T2 stage lung cancer. Combined sPLA2-IIa, CEA, and Cyfra21.1 tests increased the sensitivity for lung cancer prediction. High level of plasma sPLA2-IIa was associated with a decreased overall cancer survival. sPLA2-IIa was overexpressed in almost all non-small cell lung cancer and in the majority of small cell lung cancer by immunohistochemistry analysis.
Our finding strongly suggests that plasma sPLA2-IIa is a potential lung biomarker to distinguish benign nodules from lung cancer and to aid lung cancer diagnosis in patients with SPNs.
[Show abstract][Hide abstract] ABSTRACT: Our previous study showed that prostate cancer cells overexpress and secrete secretory phospholipases A2 group IIa (sPLA2-IIa) and plasma sPLA2-IIa was elevated in prostate cancer patients. The current study further explored the underlying mechanism of sPLA2-IIa overexpression and the potential role of sPLA2-IIa as a prostate cancer biomarker.
Plasma and tissue specimens from prostate cancer patients were analyzed for sPLA2-IIa levels. Regulation of sPLA2-IIa expression by Heregulin-α was determined by Western blot and reporter assay.
We found that Heregulin-α enhanced expression of the sPLA2-IIa gene via the HER2/HER3-elicited pathway. The EGFR/HER2 dual inhibitor Lapatinib and the NF-kB inhibitor Bortezomib inhibited sPLA2-IIa expression induced by Heregulin-α. Heregulin-α upregulated expression of the sPLA2-IIa gene at the transcriptional level. We further confirmed that plasma sPLA2-IIa secreted by mouse bearing human prostate cancer xenografts reached detectable plasma concentrations. A receiver operating characteristic (ROC) analysis of patient plasma specimens revealed that high levels of plasma sPLA2-IIa, with the optimum cutoff value of 2.0 ng/ml, were significantly associated with high Gleason score (8-10) relative to intermediate Gleason score (6-7) prostate cancers and advanced relative to indolent cancers. The area under the ROC curve (area under curve, AUC) was 0.73 and 0.74, respectively.
We found that Heregulin-α, in addition to EGF, contributes to sPLA2-IIa overexpression in prostate cancer cells. Our findings support the notion that high levels of plasma sPLA2-IIa may serve as a poor prognostic biomarker capable of distinguishing aggressive from indolent prostate cancers, which may improve decision-making and optimize patient management.
The Prostate 11/2011; 72(10):1140-9. · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our previous study revealed that Vav3 oncogene and secretory phospholipase A2-IIa (sPLA2-IIa) are overexpressed in androgen-independent prostate cancer cells relative to their androgen-dependent counterparts and contribute to development of hormone refractory prostate cancer. Vav3 is a multiple function protein with both signaling molecule and coactivator activities. sPLA2-IIa is a downstream effector of HER/HER2-PI3K-Akt-NF-κB signaling and involved in inflammatory response and tumorigenesis. The aim of the current study was to determine whether Vav3 is involved in up-regulation of sPLA2-IIa expression, given that Vav3 signals in the HER/HER2-elicited pathway. Among 46 prostate cancer specimens examined, Vav3 and sPLA2-IIa are overexpressed in 48 and 83% human prostate cancers, respectively. Vav3 overexpression is significantly associated with a high level expression of sPLA2-IIa. In addition, significant Vav3 nuclear localization is observed in two prostate cancer specimens, supporting a coactivator activity in prostate cancer cells. Further analysis revealed that Vav3 up-regulates expression of the sPLA2-IIa gene at the transcriptional level via HER/HER2-PI3K-Akt-NF-κB signaling. These data revealed that Vav3 overexpression as an additional underlying mechanism contributes to elevated sPLA2-IIa expression in prostate cancer.
[Show abstract][Hide abstract] ABSTRACT: The NF-κB is best known for its role in inflammation. Here we show that constitutive NF-κB activity in cancer cells promotes the biosynthesis of redox scavenger glutathione (GSH), which in turn confers resistance to oxidative stress. Inhibition of NF-κB significantly decreases GSH in several lines of human leukemia and prostate cancer cells possessing high or moderate NF-κB activities. Concomitantly, NF-κB inhibition by pharmacological and molecular means sensitizes "NF-κB positive" cancer cells to chemically-induced oxidative stress and death. We propose that inhibition of NF-κB can reduce intracellular GSH in "NF-κB-positive" cancers thereby improving the efficacy of oxidative stress-based anti-cancer therapy.
Cancer letters 12/2010; 299(1):45-53. · 4.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to further characterize cell growth-inhibitory effects of a recently identified androgen receptor (AR) signaling inhibitor 6-amino-2-[2-(4-tert-butyl-pnenoxy)-ethylsulfanyl]-1H-pyrimidin-4-one (DL3)(5) and antiandrogen bicalutamide (Bic). DL3 was more potent than Bic in induction of G1 arrest and reduction of G1-related cell cycle protein expression in AR-positive LNCaP cells. DL3, but not Bic, moderately inhibited growth of AR-negative PC-3 cells independent of G1 arrest. The data indicated that DL3 inhibit cell growth in both AR-dependent and -independent manners and is potentially a potent therapeutic agent for the management of advanced human prostate cancer.
Cancer letters 12/2010; 298(2):250-7. · 4.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The majority of prostate cancers are indolent, whereas a significant portion of patients will require systemic treatment during the course of their disease. To date, only high Gleason scores are best associated with a poor prognosis in prostate cancer. No validated serum biomarker has been identified with prognostic power. Previous studies showed that secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in almost all human prostate cancer specimens and its elevated levels are correlated with high tumor grade. Here, we found that sPLA2-IIa is overexpressed in androgen-independent prostate cancer LNCaP-AI cells relative to their androgen-dependent LNCaP cell counterparts. LNCaP-AI cells also secrete significantly higher levels of sPLA2-IIa. Blocking sPLA2-IIa function compromises androgen-independent cell growth. Inhibition of the ligand-induced signaling output of the HER network, by blocking PI3K-Akt signaling and the nuclear factor-kappaB (NF-κB)-mediated pathway, compromises both sPLA2-IIa protein expression and secretion, as a result of downregulation of sPLA2-IIa promoter activity. More importantly, we demonstrated elevated serum sPLA2-IIa levels in prostate cancer patients. High serum sPLA2-IIa levels are associated significantly with high Gleason score and advanced disease stage. Increased sPLA2-IIa expression was confirmed in prostate cancer cells, but not in normal epithelium and stroma by immunohistochemistry analysis. We showed that elevated signaling of the HER/HER2-PI3K-Akt-NF-κB pathway contributes to sPLA2-IIa overexpression and secretion by prostate cancer cells. Given that sPLA2-IIa overexpression is associated with prostate development and progression, serum sPLA2-IIa may serve as a prognostic biomarker for prostate cancer and a potential surrogate prostate biomarker indicative of tumor burden.
[Show abstract][Hide abstract] ABSTRACT: For early cancer diagnosis and treatment, a nanocarrier system is designed and developed with key components uniquely structured at nanoscale according to medical requirements. For imaging, quantum dots with emissions in the near-infrared range (∼800 nm) are conjugated onto the surface of a nanocomposite consisting of a spherical polystyrene matrix (∼150 nm) and the internally embedded, high fraction of superparamagnetic Fe(3)O(4) nanoparticles (∼10 nm). For drug storage, the chemotherapeutic agent paclitaxel (PTX) is loaded onto the surfaces of these composite multifunctional nanocarriers by using a layer of biodegradable poly(lactic-co-glycolic acid) (PLGA). A cell-based cytotoxicity assay is employed to verify successful loading of pharmacologically active drug. Cell viability of human, metastatic PC3mm2 prostate cancer cells is assessed in the presence and absence of various multifunctional nanocarrier populations using the MTT assay. PTX-loaded composite nanocarriers are synthesized by conjugating anti-prostate specific membrane antigen (anti-PSMA) for targeting. Specific detection studies of anti-PSMA-conjugated nanocarrier binding activity in LNCaP prostate cancer cells are carried out. LNCaP cells are targeted successfully in vitro by the conjugation of anti-PSMA on the nanocarrier surfaces. To further explore targeting, the nanocarriers conjugated with anti-PSMA are intravenously injected into tumor-bearing nude mice. Substantial differences in fluorescent signals are observed ex vivo between tumor regions treated with the targeted nanocarrier system and the nontargeted nanocarrier system, indicating considerable targeting effects due to anti-PSMA functionalization of the nanocarriers.
[Show abstract][Hide abstract] ABSTRACT: Our previous studies revealed that Vav3 oncogene is overexpressed in human prostate cancer, enhances androgen receptor (AR)-mediated signaling, and may play a role in prostate cancer development and progression. The purpose of this study was to determine the molecular mechanisms responsible for AR activation by Vav3. We found that interaction between N-terminus and C-terminus of AR is essential for its elevated activity stimulated by Vav3. The DH and PH domains of Vav3 are involved in direct interaction with AR. Both cytoplasmic and nuclear levels of AR and Vav3 are elevated and their nuclear localization is further stimulated by DHT in androgen-independent LNCaP-AI cells relative to their parental androgen-dependent LNCaP cells. Vav3 is colocalized with AR, phospho(P)-Akt, and HER2 with a short term stimulation by EGF and DHT. PI3K inhibitor LY294002 blocks colocalization of Vav3 with P-Akt. Consistently, EGF and DHT stimulate Vav3 and AR interaction and enhance PI3K-Akt signaling. Mutation of tyrosines to phenylalanines in the acidic domain or deletion of the SH2 and SH3 domains significantly enhances Vav3 ability for AR activation, while deletion of the DH domain abolishes this activity. Given that an elevated interaction of Vav3 with AR, P-Akt, and HER2 in both cytoplasm and nucleus upon the short-term of DHT stimulation, our data suggest that Vav3 may enhance non-genomic AR activity via PI3K-Akt signaling in addition to AR transcriptional activity and further support a role in androgen-independent growth in prostate cancer.
International Journal of Oncology 03/2010; 36(3):623-33. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Magnesium (Mg) as a biodegradable metal has potential advantages as an implant material. This paper studies the effect of magnesium ions on osteoblast (U2-OS) behavior since magnesium implants mainly dissolve as divalent magnesium ions (Mg(2+)). A real-time monitoring technique based on electric cell-substrate impedance sensing (ECIS) was used for measuring cell proliferation, migration, adhesion, and cytotoxicity in magnesium-conditioned media. The impedance results show that U2-OS proliferation and adhesion were inhibited in not only a magnesium-free medium but also in a medium with a high concentration of magnesium. The impedance method produced more sensitive results than the output of an MTT assay. Other standard bioanalytical tests were conducted for comparison with the ECIS method. Immunochemistry was carried out to study cell adhesion in magnesium-conditioned media by staining using F-actin and alpha-tubulin and correlated cell density on the electrode with impedance. Bone tissue formation was studied using von Kossa staining and indicated the mineralization level of cells in magnesium-conditioned media decreased with the increase of magnesium ion concentration. Real-time PCR provided gene expression indicators of cell growth, apoptosis, inflammation, and migration. Compared to the bioanalytical methods of immunochemistry and MTT assays, which need preparation time and post-washing step, ECIS was able to measure cell activity in real time without any cell culture modification. In summary, ECIS might be an effective way to study biodegradable magnesium implants.
Analytical and Bioanalytical Chemistry 03/2010; 396(8):3009-15. · 3.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Heat shock protein (hsp) 70-1 (hsp70-1) is overexpressed in human prostate cancer cells and may play important roles in prostate cancer resistance to conventional therapies. The purpose of this study was to investigate whether androgen receptor (AR) and its signaling regulate hsp70-1 expression. Several lines of AR-positive (LNCaP, LAPC-4, and 22Rv1) and -negative (PC-3, DU145, WPE1-NB14 and WPE1-NB-26) human prostatic cells were used in the study. Dihydrotestosterone (DHT) enhanced hsp70-1 expression in LNCaP cells. Expression of hsp70-1 in LNCaP cells was downregulated by the anti-androgens bicalutamide (Bic), and flutamide (Flut), and a newly identified AR signaling antagonist DL3. The downregulation of hsp70-1 by DL3 was also observed in LAPC-4 and 22Rv1 cells, but not in the four lines of AR-negative cells examined. Expression of hsp70-1 was also reduced by DL3 in PC-3 cells engineered with AR. On the other hand, knocking down AR in LNCaP cells by siRNA moderately reduced hsp70-1 level and abolished effects of DL3 on hsp70-1 expression. DL3 reduced hsp70-1 mRNA synthesis in cells and its in vitro gene transcription but did not significantly alter the stabilities of hsp70-1 mRNA and protein. Chromatin-immunoprecipitation (ChIP) assay showed that AR bound to the promoter region of HSPA1B gene, which was reduced in cells treated with DL3 or Bic. These data suggest that AR and its signaling regulate hsp70-1 expression in prostate cancer cells and that HSPA1B could be an AR target gene.
International Journal of Oncology 02/2010; 36(2):459-67. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A biosensor is an electronic device that measures biologically important parameters. An example is a sensor that measures the chemicals and materials released during corrosion of a biodegradable magnesium implant that impact surrounding cells, tissues and organs. A responsive biosensor is a biosensor that responds to its own measurements. An example is a sensor that measures the corrosion of an implant and automatically adjusts (slows down or speeds up) the corrosion rate. The University of Cincinnati, the University of Pittsburgh, North Carolina A&T State University, and the Hannover Medical Institute are collaborators in an NSF Engineering Research Center (ERC) for Revolutionizing Metallic Biomaterials (RBM). The center will use responsive sensors in experimental test beds to develop biodegradable magnesium implants. Our goal is to develop biodegradable implants that combine novel bioengineered materials based on magnesium alloys, miniature sensor devices that monitor and control the corrosion, and coatings that slow corrosion and release biological factors and drugs that will promote healing in surrounding tissues. Responsive biosensors will monitor what is happening at the interface between the implant and tissue to ensure that the implant is effective, biosafe, and provides appropriate strength while degrading. Corrosion behavior is a critical factor in the design of the implant. The corrosion behavior of implants will be studied using biosensors and through mathematical modeling. Design guidelines will be developed to predict the degradation rate of implants, and to predict and further study toxicity arising from corrosion products (i.e., Mg ion concentrations, pH levels, and hydrogen gas evolution). Knowing the corrosion rate will allow estimations to be made of implant strength and toxicity risk throughout the degradation process.
ASME 2009 International Mechanical Engineering Congress and Exposition (IMECE2009); 11/2009