Stimulation of prostate cancer cell proliferation by bone-derived factors.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 32-32
Author(s):  
P. Sluka ◽  
G. Whitty ◽  
I. D. Davis
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cell Survival ◽  
Cell Lines ◽  
Mrna Level ◽  
Receptor Expression ◽  
Cancer Cell Proliferation ◽  
Lncap Cells ◽  
Du145 Cells ◽  
And Migration

32 Background: Interactions between cancer cells and their microenvironment affect the establishment and metastasis of cancer. The most common site of prostate cancer (PC) metastasis is bone. This study examined the effects of selected factors known to be produced by bone stroma (EGF, aFGF, HGF, β-NGF, TGF-β, and TNFα) on the proliferation of PC cells. The effect of cell culture medium (CM) conditioned by osteoblasts (OBCM) was also examined. Methods: The PC-derived cell lines PC3, LNCaP, and DU145 were used. Expression of receptors for the above-mentioned cytokines was assessed using real-time RT-PCR. After 5 days of continuous cytokine treatment, proliferation was assessed by MTS conversion, and cell survival and apoptosis was assessed by 7-AAD staining and flow cytometry. OBCM was generated using the HOS, MG63, and SaOs2 cell lines. CM from the HT1080 fibrosarcoma cell line was used as a non-bone control. Results: The PC cell lines expressed receptors for all of the cytokines examined at the mRNA level. LNCaP cell proliferation was increased by aFGF and decreased by TGF-β. Treatment with TNFα decreased proliferation of all PC cell lines. These effects were not due to apoptosis. EGF, HGF, and β-NGF did not affect proliferation of any line despite receptor expression. OBCM increased proliferation of PC3 and DU145 cells but not LNCaP cells, while HT1080 CM did not affect proliferation of any line. Conclusions: PC cells are able to respond to defined bone-derived factors and that the nature of this response varies between individual cancers. Acidic FGF increased proliferation of LNCaP cells while TGF-β and TNFα decreased proliferation of LNCaP and all cell lines, respectively; an effect not mediated by apoptosis. Current studies are examining the effect of these cytokines on other functional parameters (cell survival, adhesion and migration) and on primary PC epithelial cells. No significant financial relationships to disclose.

ARFGAP3 an androgen target gene promotes prostate cancer cell proliferation and migration.

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Cell Biology ◽  
Adaptor Protein ◽  
Cancer Cell Proliferation ◽  
Lncap Cells ◽  
Gtpase Activating Protein ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

ADP ribosylation factor GTPase-activating protein 3 (ARFGAP3) is a GTPase-activating protein that associates with the Golgiapparatus and regulates the vesicular trafficking pathway. In the present study, we examined the contribution of ARFGAP3 toprostate cancer cell biology. We showed that ARFGAP3 expression was induced by 100 nM of dihydrotestosterone (DHT) atboth the mRNA and protein levels in androgen-sensitive LNCaP cells. We generated stable transfectants of LNCaP cells withFLAG-tagged ARFGAP3 or a control empty vector and showed that ARFGAP3 overexpression promoted cell proliferation andmigration compared with control cells. We found that ARFGAP3 interacted with paxillin, a focal adhesion adaptor protein thatis important for cell mobility and migration. Small interfering RNA (siRNA)-mediated knockdown of ARFGAP3 showed thatARFGAP3 siRNA markedly reduced LNCaP cell growth. Androgen receptor (AR)-dependent transactivation activity on prostatespecificantigen (PSA) enhancer was synergistically promoted by exogenous ARFGAP3 and paxillin expression, as shown byluciferase assay in LNCaP cells. Thus, our results suggest that ARFGAP3 is a novel androgen-regulated gene that can promoteprostate cancer cell proliferation and migration in collaboration with paxillin.

scholarly journals Expression and Function of Lysophosphatidic Acid LPA1 Receptor in Prostate Cancer Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4883-4892 ◽  
Author(s):  
Rishu Guo ◽  
Elizabeth A. Kasbohm ◽  
Puneeta Arora ◽  
Christopher J. Sample ◽  
Babak Baban ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Lysophosphatidic Acid ◽  
Cell Cycle Progression ◽  
Receptor Activation ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
And Migration

The bioactive phospholipid lysophosphatidic acid (LPA) promotes cell proliferation, survival, and migration by acting on cognate G protein-coupled receptors named LPA1, LPA2, and LPA3. We profiled gene expression of LPA receptors in androgen-dependent and androgen-insensitive prostate cancer cells and found that LPA1 gene is differentially expressed in androgen-insensitive and LPA-responsive but not androgen-dependent and LPA-resistant cells. In human prostate specimens, expression of LPA1 gene was significantly higher in the cancer compared with the benign tissues. The androgen-dependent LNCaP cells do not express LPA1 and do not proliferate in response to LPA stimulation, implying LPA1 transduces cell growth signals. Accordingly, stable expression of LPA1 in LNCaP cells rendered them responsive to LPA-induced cell proliferation and decreased their doubling time in serum. Implantation of LNCaP-LPA1 cells resulted in increased rate of tumor growth in animals compared with those tumors that developed from the wild-type cells. Growth of LNCaP cells depends on androgen receptor activation, and we show that LPA1 transduces Gαi-dependent signals to promote nuclear localization of androgen receptor and cell proliferation. In addition, treatment with bicalutamide inhibited LPA-induced cell cycle progression and proliferation of LNCaP-LPA1 cells. These results suggest the possible utility of LPA1 as a drug target to interfere with progression of prostate cancer.

Role of GADD45α as a potential therapeutic target for prostate cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10566-10566
Author(s):  
R. Singal ◽  
K. Ramachandran ◽  
G. Gopisetty ◽  
L. Navarro ◽  
E. Gordian ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Therapeutic Target ◽  
Recombinant Expression ◽  
Proximal Promoter ◽  
Lncap Cells ◽  
Potential Therapeutic Target ◽  
Du145 Cells ◽  
Docetaxel Chemotherapy

10566 Background: Defects in the apoptotic pathway contribute to uncontrolled cell proliferation of cancer cells and confer resistance to chemotherapeutic drugs. Understanding the mechanisms of deregulation of apoptosis related genes would enable targeted treatment methods to improve the efficacy of chemotherapy. Growth Arrest and DNA Damage inducible, alpha (GADD45a) mediates cytotoxicity of docetaxel chemotherapy. We examined the mechanism of regulation of GADD45a in prostate cancer cells and the effect of its upregulation on sensitivity to docetaxel chemotherapy. Methods: Levels of GADD45a in Du145, LNCaP and PC3 were analyzed by real time reverse transcriptase PCR and western blotting. DNA methylation was studied by bisulfite sequencing. Chromatin immunoprecipitation was used to study interaction of methyl binding proteins to GADD45 5’ sequence. Cytotoxicity after drug treatment was measured by MTT cell proliferation assay. Apoptosis assays were done by Annexin V/propidium iodide staining followed by flow cytometry. Results: Levels of expression of GADD45a in Du145 and LNCaP cells were lower than that in PC3. A 4 CpG region upstream of the proximal promoter region was methylated in Du145 and LNCaP cells. Methylation was reversed by treatment of Du145 and LNCaP cells with DNA methyl transferase (DNMT) inhibitors such as 5- Azacytidine or 5- Aza deoxycytidine leading to reactivation of GADD45a expression in these cells. This region was also frequently methylated in prostate cancer tissues. Methyl binding protein, MeCP2 was associated with the methylated 4 CpGs in Du145 and knock down of MeCP2 by transfection of MeCP2 siRNA vector in Du145 cells (Du145-MeCP2-ve) led to increased expression of GADD45a, without affecting the methylation status of the gene. Enhanced sensitivity to docetaxel was observed by upregulation of GADD45a in Du145 cells by (a) recombinant expression of GADD45a (b) downregulation of MeCP2 and (c) pretreatment with 5-Azacytidine. Conclusions: GADD45a is frequently deregulated in prostate cancer by methylation of 5’ 4 CpG region and is a potential therapeutic target for treatment of prostate cancer. [Table: see text]

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