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PubMed2006

The splicing factor crooked neck associates with the RNA-binding protein HOW to control glial cell maturation in Drosophila.

In both vertebrates and invertebrates, glial cells wrap axonal processes to ensure electrical conductance. Here we report that Crooked neck (Crn), the Drosophila homolog of the yeast Clf1p splicing factor, is directing peripheral glial cell maturation. We show that crooked neck is expressed and required in glial cells to control migration and axonal wrapping. Within the cytoplasm, Crn interacts with the RNA-binding protein HOW and then translocates to the nucleus where the Crn/HOW complex controls glial differentiation by facilitating splicing of specific target genes. By using a GFP-exon trap approach, we identified some of the in vivo target genes that encode proteins localized in autocellular septate junctions. In conclusion, here we show that glial cell differentiation is controlled by a cytoplasmic assembly of splicing components, which upon translocation to the nucleus promote the splicing of genes involved in the assembly of cellular junctions.

Animals↗
PubMed2006

Electrospun mat of tyrosine-derived polycarbonate fibers for potential use as tissue scaffolding material.

Desaminotyrosyl-tyrosine ethyl ester (DTE) and desaminotyrosyl-tyrosine (DT) were used as monomers in the synthesis of two tyrosine-derived polycarbonates: the slow degrading homopolymer poly(DTE carbonate) and the fast degrading co-polymer poly(DTE-co-20%DT carbonate). Ultrafine fibers of these polymers were successfully fabricated using an electrospinning process. The effects of some solution and process parameters (i.e., polymer concentration, electrostatic field strength and solvent system) on morphological appearance and diameters of the obtained fibers were investigated by scanning electron microscopy (SEM). Smooth fibers were obtained at high enough solution concentrations (i.e., 15 and 20% (w/v)). The average fiber diameter was found to increase with increasing polymer concentration and applied electrostatic field strength. The electrospinnability of poly(DTE-co-20%DT carbonate) in dichloromethane was enhanced when methanol was used as the co-solvent. In all of the conditions investigated, the average diameter of the obtained smooth fibers ranged between 1.9 and 5.8 microm. A qualitative assessment of an as-spun mat of poly(DTE carbonate) fibers as a tissue scaffolding material showed that three different cultured cell lines appeared to adhere and propagate well within the scaffold. For poly(DTE carbonate) exceptionally high cell densities could be achieved after 10 days of cell culture.

Animals↗
PubMedDate not supplied

Endothelial p21(WAF1/CiP1) cell cycle inhibitor is down-regulated in breast cancer.

BACKGROUND: Tumor angiogenesis is considered a multi-pathway process, while p21(WAF1/CiP1) is a CDK inhibitor involved in cell division and survivaL Herein the tumor environment effect on endothelial p21(WAF1/Cip1) expression is examined. MATERIALS AND METHODS: The EA.hy 926 endothelial cell line and tumor-conditioned medium (TCM) from the MDA-MB-468 breast cancer cell line were used. Endothelial cells grown alone and in TCM were immunostained for p21(WAF1/Cip1) and analyzed by RT-PCR Forty-four cases of breast cancer and forty-three cases of normal breast tissue were immunostained for p21(WAF1/Cip1). RESULTS: Endothelial p21(WAF1/Cip1) is transcriptionally down-regulated under the influence of TCM. Moreover, it seems that breast cancer tumor endothelium does not express p21(WAF1/Cip1). CONCLUSION: P21(WAF1/Cip1) plays a major role in angiogenesis, since tumor cells seem to down-regulate endothelial p21(WAF1/Cip1), compared to endothelial cells grown in serum-free medium. The verification of the tissue culture experiment results by immunohistochemistry on tissue sections indicates p21(WAF1/Cip1) as a target of modern molecular therapy.

Breast Neoplasms↗
PubMed2005

Nuclear factor-kappaB-dependent mechanisms in breast cancer cells regulate tumor burden and osteolysis in bone.

A central mediator of a wide host of target genes, the nuclear factor-kappaB (NF-kappaB) family of transcription factors, has emerged as a molecular target in cancer and diseases associated with bone destruction. To evaluate how NF-kappaB signaling in tumor cells regulates processes associated with osteolytic bone tumor burden, we stably infected the bone-seeking MDA-MB-231 breast cancer cell line with a dominant-negative mutant IkappaB that prevents phosphorylation of IkappaBalpha and associated nuclear translocation of NF-kappaB. Blockade of NF-kappaB signaling in MDA-MB-231 cells by the mutant IkappaB decreased in vitro cell proliferation, expression of the proinflammatory, bone-resorbing cytokine interleukin-6, and in vitro bone resorption by tumor/osteoclast cocultures while reciprocally up-regulating production of the proapoptotic enzyme caspase-3. Suppression of NF-kappaB transcription in these breast cancer cells also reduced incidence of in vivo tumor-mediated osteolysis after intratibial injection of tumor cells in female athymic nude mice. Immunohistochemistry showed that the cancerous lesions formed in bone by MDA-MB-231 cells express both interleukin-6 and the p65 subunit of NF-kappaB at the bone-tumor interface. NF-kappaB signaling in breast cancer cells therefore promotes bone tumor burden and tumor-mediated osteolysis through combined control of tumor proliferation, cell survival, and bone resorption. These findings imply that NF-kappaB and its associated genes may be relevant therapeutic targets in osteolytic tumor burden.

Animals↗
PubMed2005

Evaluating hypoxia-inducible factor-1alpha as a cancer therapeutic target via inducible RNA interference in vivo.

Validating potential targets is an important step in the drug discovery process. In this study, we tested the feasibility of using inducible RNA interference (RNAi) in vivo to obtain an unbiased evaluation on the efficacy of inhibiting hypoxia-inducible factor-1alpha (HIF-1alpha) in established tumors. We showed that HIF-1alpha inhibition resulted in transient tumor stasis or tumor regression, and inhibiting HIF-1alpha in early-stage tumors was found to be more efficacious than inhibiting HIF-1alpha in more established tumors. A differential requirement of HIF-1alpha for tumor growth was also observed among different tumor types. Examination of tumors resistant to HIF-1alpha inhibition suggested that the resistance might result from a less hypoxic tumor environment and the level of HIF-1alpha expression in tumors may be a useful marker for predicting tumor response to HIF-1 inhibition. This study shows that inducible RNAi is a versatile tool for evaluating cancer targets in vivo. In addition to broad implications on in vivo validation of cancer targets, results from this study will also be instructive for practical applications of HIF-1-based cancer therapeutics.

Animals↗
PubMed2006

Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation.

It has been proposed that cannabinoids are involved in the control of cell fate. Thus, these compounds can modulate proliferation, differentiation, and survival in different manners depending on the cell type and its physiopathologic context. However, little is known about the effect of cannabinoids on the cell cycle, the main process controlling cell fate. Here, we show that Delta(9)-tetrahydrocannabinol (THC), through activation of CB(2) cannabinoid receptors, reduces human breast cancer cell proliferation by blocking the progression of the cell cycle and by inducing apoptosis. In particular, THC arrests cells in G(2)-M via down-regulation of Cdc2, as suggested by the decreased sensitivity to THC acquired by Cdc2-overexpressing cells. Of interest, the proliferation pattern of normal human mammary epithelial cells was much less affected by THC. We also analyzed by real-time quantitative PCR the expression of CB(1) and CB(2) cannabinoid receptors in a series of human breast tumor and nontumor samples. We found a correlation between CB(2) expression and histologic grade of the tumors. There was also an association between CB(2) expression and other markers of prognostic and predictive value, such as estrogen receptor, progesterone receptor, and ERBB2/HER-2 oncogene. Importantly, no significant CB(2) expression was detected in nontumor breast tissue. Taken together, these data might set the bases for a cannabinoid therapy for the management of breast cancer.

Apoptosis↗
PubMed1997

Perlecan regulates Oct-1 gene expression in vascular smooth muscle cells.

Vascular smooth muscle cells (SMCs) are very quiescent in the mature vessel and exhibit a remarkable phenotype-dependent diversity in gene expression that may reflect the growth responsiveness of these cells under a variety of normal and pathological conditions. In this report, we describe the expression pattern of Oct-1, a member of a family of transcription factors involved in cell growth processes, in cultured and in in vivo SMCs. Oct-1 mRNA was undetectable in the contractile-state in vivo SMCs; was induced upon disruption of in vivo SMC-extracellular matrix interactions; and was constitutively expressed by cultured SMCs. Oct-1 transcripts were repressed when cultured SMCs were plated on Engelbreth-Holm-Swarm tumor-derived basement membranes (EHS-BM) but were rapidly induced after disruption of SMC-EHS-BM contacts; reexpression was regulated at the transcriptional level. To identify the EHS-BM component involved in the active repression of Oct-1 mRNA expression, SMCs were plated on laminin, type IV collagen, fibronectin, or perlecan matrices. Oct-1 mRNA levels were readily detectable when SMCs were cultured on matrices composed of laminin, type IV collagen, or fibronectin but were repressed when SMCs were cultured on perlecan matrices. Finally, the Oct-1-suppressing activity of EHS-BM was sensitive to heparinase digestion but not to chondroitinase ABC or hyaluronidase digestion, suggesting that the heparan sulfate side chains of perlecan play a biologically important role in negatively regulating the expression of Oct-1 transcripts.

Animals↗
PubMed2005

A novel function for galectin-7: promoting tumorigenesis by up-regulating MMP-9 gene expression.

Metastasis is a multistep process by which cancer cells, after acquiring several capabilities, spread to distinct sites in the body. It is the major cause of death in individuals suffering from cancer. We have recently identified galectin-7 as a new gene associated with the progression of T cell lymphoma toward a metastatic phenotype, suggesting a possible causal relationship. The present study was designed to investigate the role of galectin-7 in lymphoma. We found that the development of thymic lymphoma was accelerated when induced by lymphoma cells overexpressing galectin-7. Moreover, transfection of an expression vector containing the galectin-7 gene in low metastatic lymphoma cells increased their metastatic behavior and confers these cells with the new ability to overcome the resistance of intercellular adhesion molecule-1-deficient mice to lymphoma dissemination. Finally, we provide data suggesting that galectin-7 modulates the aggressive behavior of lymphoma cells by controlling the expression of metastatic genes, such as MMP-9. This hypothesis is based on the following evidence: (a) galectin-7 transfectants have higher levels of MMP-9 expression, (b) addition of beta-lactose completely inhibits expression of MMP-9 by galectin-7 transfectants, and (c) recombinant forms of galectin-7 induces the expression of MMP-9 in both mouse and human lymphoma cells. Our results have uncovered the existence of a previously undescribed activity, the promotion of cancer cell malignancy, to galectin-7.

Animals↗
PubMed2005

Rac3-mediated transformation requires multiple effector pathways.

Our initial characterization of Rac3, a close relative of the small GTPase Rac1, established its ability to promote membrane ruffling, transformation, and activation of c-jun transcriptional activity. The finding that Rac3 is transforming, and its similarity to Rac1, a protein that has a well-established connection to many processes important for cancer progression, prompted further investigation into Rac3 transformation. We used effector domain mutants (EDMs) to explore the relationship among Rac signaling, transformation, and effector usage. All Rac3 EDMs tested (N26D, F37L, Y40C, and N43D) retained the ability to promote membrane ruffling and focus formation. In contrast, only the N43D mutant promoted anchorage independence. This differs from Rac1, where both N26D and N43D mutants were impaired in both types of transformation. To learn more about the signaling pathways involved, we did luciferase reporter assays and glutathione S-transferase pull-down assays for effector binding. We found evidence for a functional link between activation of phospholipase Cbeta2 by Rac3 and signaling to the serum response factor (SRF). Surprisingly, we also found that Rac3 binds poorly to the known Rac1 effectors mixed lineage kinases 2 and 3 (MLK2 and MLK3). Transcription of cyclin D1 was the only pathway that correlated with growth in soft agar. Our experiments show that activation of membrane ruffling and transcriptional activation of c-jun, SRF, or E2F are not sufficient to promote anchorage-independent growth mediated by Rac3. Instead, multiple effector pathways are required for Rac3 transformation, and these overlap partially but not completely with those used by Rac1.

Animals↗
PubMed2007

Malignant transformation of the cultured human normal biliary tract epithelial cells induced by hepatitis C virus core protein.

High level expression of hepatitis C virus core protein (HCV-C) was detected in hilar cholangiocarcinoma tissues in our previous studies. This protein played an important role in the process of cancer cell inversion and proliferation, by some direct and indirect effects on certain genes. Based on this observation, we investigated the effect of HCV-C on human normal biliary epithelial (hBE) cell transformation and tumor development. Plasmid pHCV-C encoding the gene of HCV core protein was constructed and transfected into hBE cells. The expression and the biological effect of HCV-C in HCV-C gene-modified hBE cells were determined in vitro and in vivo. The clone formation rates of hBE cells transfected with pHCV-C, pcdna3.1 and mock-transfected cells were 36, 2.5 and 1.5%, respectively. Tumor developed in 7 of 7 nude mice after incubated with pHCV-C transfected hBE cells, while no tumor appeared in mice injected with pcdna3.1- and mock-transfected hBE cells. To investigate the possible mechanism of malignant transformation, we further studied the telomerase activity and human telomerase reverse transcriptase (hTERT) expression in pHCV-C transfected hBE cells. The elevated expression of hTERT was confirmed by RT-PCR, immunocytochemistry (ICC) and Western blot analysis, which in turn elevated the telomerase activity, confirmed by TRAP-ELISA. These results indicated that HCV-C protein could participate in malignant transformation of human normal biliary epithelial cells and induce cholangiocarcinoma tumorigenesis, and the activation of telomerase was one of the possible mechanisms.

Animals↗
PubMed2002

The regulation of actin organization by actin-depolymerizing factor in elongating pollen tubes.

Pollen tube elongation is a polarized cell growth process that transports the male gametes from the stigma to the ovary for fertilization inside the ovules. Actomyosin-driven intracellular trafficking and active actin remodeling in the apical and subapical regions of pollen tubes are both important aspects of this rapid tip growth process. Actin-depolymerizing factor (ADF) and cofilin are actin binding proteins that enhance the depolymerization of microfilaments at their minus, or slow-growing, ends. A pollen-specific ADF from tobacco, NtADF1, was used to dissect the role of ADF in pollen tube growth. Overexpression of NtADF1 resulted in the reduction of fine, axially oriented actin cables in transformed pollen tubes and in the inhibition of pollen tube growth in a dose-dependent manner. Thus, the proper regulation of actin turnover by NtADF1 is critical for pollen tube growth. When expressed at a moderate level in pollen tubes elongating in in vitro cultures, green fluorescent protein (GFP)-tagged NtADF1 (GFP-NtADF1) associated predominantly with a subapical actin mesh composed of short actin filaments and with long actin cables in the shank. Similar labeling patterns were observed for GFP-NtADF1-expressing pollen tubes elongating within the pistil. A Ser-6-to-Asp conversion abolished the interaction between NtADF1 and F-actin in elongating pollen tubes and reduced its inhibitory effect on pollen tube growth significantly, suggesting that phosphorylation at Ser-6 may be a prominent regulatory mechanism for this pollen ADF. As with some ADF/cofilin, the in vitro actin-depolymerizing activity of recombinant NtADF1 was enhanced by slightly alkaline conditions. Because a pH gradient is known to exist in the apical region of elongating pollen tubes, it seems plausible that the in vivo actin-depolymerizing activity of NtADF1, and thus its contribution to actin dynamics, may be regulated spatially by differential H(+) concentrations in the apical region of elongating pollen tubes.

Actins↗
PubMed2006

Engineering eukaryotic signal transduction with RNAi: enhancing Drosophila S2 cell growth and recombinant protein synthesis via silencing of TSC1.

RNAi has been useful in the study of biochemical pathways, but has not been widely used as a tool in metabolic engineering. The work described here makes use of double-stranded RNA (dsRNA) for the post-transcriptional gene silencing of TSC1 in Drosophila S2 cells. TSC1 downregulates the insulin-mediated signal transduction pathway, and serves as a metabolic control to guard against cellular overproliferation and tumorogenesis in both flies and mammals. By silencing TSC1 with in vitro-synthesized dsRNA, we have created a tunable and specific metabolic "throttle" that, like insulin, apparently increases the specific growth rate of S2 cells in a dose-dependent manner. This "throttle," augments the benefits of insulin addition while apparently avoiding deleterious and pleiotropic effects which can lead to lysis. During the period wherein dsRNA was active, cell growth rate was increased by 11% by the addition of 15 microg/mL dsTSC1 and by over 20% by the addition of 30 microg/mL dsTSC1. Additionally, synthesis of recombinant green fluorescent protein (GFP) was increased nearly 50% in a stable S2 cell line inducibly expressing GFP. Accordingly, we have "tuned" a normally tumorogenic pathway in animals into an advantage for both growth and recombinant product synthesis in cell culture. Potential applications for improving eukaryotic cell culture are anticipated.

Animals↗
PubMed2006

The role of constitutively active signal transducer and activator of transcription 3 in ovarian tumorigenesis and prognosis.

BACKGROUND: Signal transducer and activator of transcription 3 (Stat3), which is a latent transcription factor that participates in the transcriptional activation of apoptosis and cell cycle progression, has been implicated as an oncogene in several neoplastic diseases. However, the specific role of Stat3 in ovarian carcinogenesis remains poorly understood. The objectives of the current study were to examine the effect of Stat3 activation on the phenotypic transformation of an immortalized, nontumorigenic ovarian epithelial cell line and to evaluate the expression of tyrosine-activated Stat3 (pStat3) in tissue microarrays from 303 ovarian carcinomas to determine its prognostic relevance and to correlate its expression with several upstream oncogenes of Stat3 and with the oncogenes involved in apoptosis and proliferation. METHODS: Overexpression of pStat3 was weakly tumorigenic and produced measurable tumors in mice in 1 of 3 clones. Using tissue microarrays from a large group of patients with primary ovarian carcinoma, the expression of pStat3 was correlated with the expression of growth factor receptors (HER-2/neu and epidermal growth factor receptor [EGFR]), interleukin 6, and the proliferation and apoptosis markers Ki-67, Bcl-2, and Bcl-xL and with clinicopathologic variables and patient survival. RESULTS: High pStat3 expression in the tumor tissue microarray was associated with high levels of HER-2/neu, EGFR, and Ki-67. No correlation was observed between overall pStat3 levels and any other clinicopathologic variables tested. High nuclear expression of pStat3 (>10% of positive-stained cells) was linked with poor overall survival. CONCLUSIONS: The activation and translocation of pStat3 to the nucleus are frequent events in ovarian carcinoma that are associated with a poor prognosis. Further studies are needed to elucidate the mechanism of activation of Stat3, its effects on downstream targets, and its role in the neoplastic transformation of epithelial ovarian cells.

Animals↗
PubMed2006

Murine spinal cord explants: a model for evaluating axonal growth and myelination in vitro.

In vitro models of myelinating central nervous system axons have mainly been of two types, organotypic or dissociated. In organotypic cultures, the tissue fragment is thick and usually requires sectioning (physically or optically) before visual examination. In dissociated cultures, tissue is dispersed across the culture surface, making it difficult to measure the extent of myelinated fiber growth. We aimed to develop a method of culturing myelinated CNS fibers in defined medium that could be 1) studied by standard immunofluorescence microscopy (i.e., monolayer type culture), 2) used to measure axonal growth, and 3) used to evaluate the effect of substrate and media components on axonal growth and myelination. We used 120-micro m slices of embryonic murine spinal cord as a focal source of CNS tissue from which myelinated axons could extend in a virtual monolayer. Explants were cultured on both poly-L-lysine and astrocytes. The latter were used because they are the scaffold on which axonal growth and myelination occurs during normal development. Outgrowth from the explant and myelination of axons was poor on poly-L-lysine but was promoted by an astrocyte bed layer. The best myelin formation occurred in defined media based on DMEM using N2 mix; it was not promoted by Sato mix or Neurobasal medium with B27 supplement. Neuronal survival was poor in serum-containing medium. This tissue culture model should facilitate the study of factors involved in promoting outgrowth of CNS axons and their myelination. As such it is relevant to studies on myelination and spinal cord repair.

Animals↗
PubMed2005

Induction of AP-1 activity by androgen activation of the androgen receptor in LNCaP human prostate carcinoma cells.

BACKGROUND: The androgen receptor and activator protein-1 (AP-1) transcription factors affect growth regulation in normal and cancerous prostate cells. Effects of androgen-activated androgen receptor on AP-1 activity were determined in the LNCaP human prostate carcinoma cell model. METHODS: Cells were exposed to 1 nM androgen +/- antiandrogen bicalutamide. Cellular growth and cell cycle effects were determined by DNA, viability, and bromodeoxyuridine (BrdU) fluorescence activated cell sorter (FACS) assays. AP-1 effects were determined by an AP-1-luciferase enzyme reporter vector for transcriptional activity, electrophoretic mobility shift assay (EMSA)/antibody supershift for DNA-binding, quantitative RT-PCR for mRNA, and immunoblot for protein. RESULTS: Androgen induced G(1) growth arrest. This growth arrest was abrogated by treatment with bicalutamide, demonstrating that growth arrest by androgen was due to androgen receptor activation. Concurrently, AP-1 DNA-binding and transcriptional activity was induced over 96 hr androgen exposure, which was also inhibited by bicalutamide. Interestingly, although no change in AP-1 transcriptional activity was observed 24 hr after androgen exposure, there was an increase in Fra-2 expression and AP-1 DNA-binding. Paradoxically, while Fra-2 mRNA and protein levels continued to increase, binding of Fra-2 to the AP-1 site decreased over 96 hr, with a concomitant increase in JunD AP-1-binding and a marked increase in expression of the 35 kDa form of JunD. Enhanced expression of this short form of JunD is a novel effect of androgen exposure that occurred during the 24-96 hr time period, as growth effects emerged. CONCLUSION: Activation of androgen receptor by androgen induces changes in AP-1 activity and AP-1 factor DNA-binding that may contribute significantly to androgen-induced changes in prostate cancer cell growth.

Androgen Antagonists↗
PubMed2005

Possible role of adaptive mutation in resistance to antiandrogen in prostate cancer cells.

BACKGROUND: Some mutations of androgen receptor (AR) confer resistance to antiandrogen to prostate cancer (PC) cells. Previously we reported that LNCaP-cxD2 cells established from androgen-dependent LNCaP-FGC PC cells as an antiandrogen bicalutamide-resistant subline harbor W741C/L mutation in the AR gene. In this report, we examined one possible mechanism of the resistance. METHODS: Change in the gene expression and the protein levels relevant to mutagenesis in LNCaP-FGC cells during bicalutamide-treatment was assessed. The AR sequence of bicalutamide-resistant LNCaP-cxD2 cells was compared with that of parental LNCaP-FGC cells. RESULTS: The expression of DNA polymerases (Pol) switched from high-fidelity subset to error-prone subset, and DNA mismatch repair proteins (MMR) were down-regulated. The rate of multiple mutations in the AR gene was higher in LNCaP-cxD2 cells than LNCaP-FGC cells. CONCLUSIONS: These results suggest the hypermutational state might occur in LNCaP-FGC cells during bicalutamide-treatment, which might create the W741C/L mutant AR leading to bicalutamide-resistance.

Androgen Antagonists↗
PubMed2005

Role of androgen receptor in the progression of human prostate tumor cells to androgen independence and insensitivity.

BACKGROUND: Various studies have implicated the androgen receptor (AR) in the progression of androgen-dependent human prostate cancer cells to androgen-independent and androgen-insensitive phenotypes, but the exact role of AR in progression is unclear. METHODS: To mimic the clinical situation and test the role of AR in progression, we cultured androgen-dependent LNCaP 104-S prostate tumor cells in the presence of the antiandrogen Casodex (bicalutamide) to derive resistant (CDXR) clones. In a second step, we cultured CDXR cells in the presence of the androgen R1881, which generated androgen- and Casodex-insensitive (IS) cells. These cells were then characterized with regard to AR function and the effect of ectopic AR expression or AR knockdown on androgen sensitivity. RESULTS: CDXR cells showed increased AR expression and transcriptional activity. CDXR cell proliferation was unaffected by Casodex but was repressed by androgen in vitro and in vivo. IS cells, on the other hand, had greatly reduced AR expression and activity compared to CDXR cells. Knockdown of AR expression in CDXR cells produced cells that were insensitive to androgen. Conversely, re-expression of AR in IS cells regenerated cells that were repressed by androgen. Knockdown of AR expression in 104-S cells produced cells that remained stimulated by androgen, while overexpression of AR in 104-S cells generated an androgen-repressed phenotype but did not confer androgen-independent growth. CONCLUSIONS: Increased AR expression determines whether prostate cancer cells are repressed by androgen, but is not required for androgen independence. These results may have implications for anti-AR therapy for prostate cancer.

Androgen Antagonists↗
PubMed2006

Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation.

BACKGROUND: Chromosomal instability is one of the most common features of prostate cancer (PC), especially in advanced stages. Recent studies suggest that defects in mitotic checkpoints play a role in carcinogenesis. Lack of mitotic regulation induces aneuploidy in cancer cells acting thereafter as a driving force for malignant progression. Serine/threonine protein kinases of the Aurora genes family play an important throughout the entire cell cycle. In that Aurora B regulates chromosome segregation by ensuring the orientation of sister chromatids. As a consequence, the overexpression of Aurora B in diploid human cells NHDF induces the appearance of multinucleate cells. METHODS: Archive samples of normal and neoplastic prostate tissue, and prostate derived cell lines were screened for the expression of Aurora B. RESULTS: Immunohistochemical analysis showed increased nuclear expression of Aurora-B in high Gleason grade PCs respect to low and intermediate grade cases and in all cancers in respect to hyperplastic and normal glands. Furthermore, in the high Gleason grade anaplastic cancer tissues Aurora B expression was accompanied by the phosphorylation of the histone H3. In analogy to the in vivo situation, Aurora B was vigorously expressed in the androgen independent PC cell lines PC3 and DU145, while a very modest expression of the kinase was observed in the androgen sensitive LnCap cells and in the EPN cells, a line of epithelial cells derived from normal prostate tissue. In addition, in PC3 cells Aurora B expression is accompanied the by the phosphorylation of the histone H3. The block of Aurora B expression induced by an inhibitor of Aurora kinase activity significantly reduced the growth of prostate carcinoma cells, but not that of non-transformed EPN cells. CONCLUSIONS: Our data are the first demonstration of a role of Aurora B in PC progression. In addition, the observation that Aurora B specific inhibitors interfere with PC cell proliferation but not with that of non-transformed prostate epithelial cells suggest that Aurora B is a potential therapeutic target for PC.

Aurora Kinase B↗