Growth inhibitory effect of p21 and p53 containing adenoviruses on transitional cell carcinoma cell lines in vitro and in vivo.
ABSTRACT Altered p53 expression has been demonstrated in the majority of advanced transitional cell carcinoma (TCC) of the bladder tumors. The objective of this investigation was to examine the effect of the introduction of a p53 or p21((WAF1/CIP1)) adenovirus on the proliferation and apoptosis of various human TCC cell lines in vitro and in vivo. Proliferation was measured by 3H-thymidine incorporation. Apoptosis was measured by DNA fragmentation and bax expression. We also examined the effect of ex vivo introduction of the p21((WAF1/CIP1)) or the p53 gene on growth of the T24 TCC cells and UMUC-3 TCC cells introduced subcutaneously into athymic nude mice. We found that although the effect of the p21-adenovirus on the proliferation of various TCC lines varied with each individual cell line, there was a substantial growth inhibition observed (greater than 80% growth inhibition) in seven of the eight TCC cell lines at the highest viral dosage. In contrast, after 24 h, the highest dosage of the p53-adenovirus produced only a heterogeneous decrease in proliferation compared to the highest dose of the p21((WAF1/CIP1))-adenovirus (40-90%). In ex vivo experiments, no tumors were found in nude mice injected subcutaneously with either TCC cell line exposed in vitro to the AdSCMV-p21((WAF1/CIP1)) or AdSCMV-p53 viruses before three weeks. There was a threefold decrease in tumor square area at week 5 in the Ad5CMV-p21((WAF1/CIP1)) or Ad5CMV-p53 TCC cells injected mice (p<0.001, p<0.009) compared to either mock or Ad5CMVLacZ TCC bladder tumor cells. These data suggest that significant portion of the effect of altered p53 on TCC phenotype may be mediated through the p21((WAF1/CIP1)) pathway. Thus, the restoration of p21((WAF1/CIP1)) function in this tumor system may be a beneficial therapeutic strategy.
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ABSTRACT: Androgen withdrawal can prolong life in men with advanced prostate cancer, but these remissions are temporary because the surviving cells progress as hormone-refractory cancer. The mechanisms that are involved in the transition of androgen-dependent prostate cancer into androgen-independent prostate cancer (AIPC) are not fully understood. To identify globally differentially expressed phosphoproteins in the androgen-independent prostate, to elucidate the molecular mechanisms that underlie the formation of AIPC and to identify new molecular targets that can be used to develop treatments for the disease. An androgen-independent LNCaP cell line, LNCaP-AI, was established using androgen ablation. Differentially expressed phosphoproteins in LNCaP cells and LNCaP-AI cells were enriched by immunoprecipitation, analyzed by 2D-PAGE and identified by MALDI-TOF MS. Total protein expression levels for two regulated proteins were confirmed by Western blot. Association network analysis was carried out using the STRING database. The phosphorylation statuses of 17 proteins were significantly (P < 0.05) different between LNCaP-AI cells and LNCaP cells. Most proteins that were identified are known to be involved in tumor progression, and several of these proteins could be constructed into an association network. A further analysis by bioinformatics indicated that P53, HSP27, and the MAPK pathway may contribute to the transition from androgen-dependence to androgen-independence. Blocking the MAPK signaling pathway may be useful in the treatment of AIPC.The Prostate 01/2009; 70(5):508-17. DOI:10.1002/pros.21085 · 3.57 Impact Factor
Chapter: Gene Therapy in UrologyGene Therapy Applications, 08/2011; , ISBN: 978-953-307-541-9
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ABSTRACT: The development of therapeutic resistance, after hormone or chemotherapy for example, is the underlying basis for most cancer deaths. Exposure to anticancer therapies induces expression of many stress related proteins, including small heat shock proteins (HSPs). HSPs interact with various client proteins to assist in their folding and enhance the cellular recovery from stress, thus restoring protein homeostasis and promoting cell survival. The vents of cell stress and cell death are linked, as the induction of molecular chaperones appears to function at key regulatory points in the control of apoptosis. On the basis of these observations and on the role of molecular chaperones in the regulation of steroid receptors, kinases, caspases, and other protein remodelling events involved in chromosome replication and changes in cell structure, it is not surprising that molecular chaperones have been implicated in the control of cell growth and in resistance to various anticancer treatments that induce apoptosis. Recently, several molecular chaperones such as Clusterin and HSP27 have been reported to be involved in development and progression of hormone-refractory prostate cancer. In this review, we address some of the molecular and cellular events initiated by treatment induced stress, and discuss the potential role of chaperone proteins as targets for prostate cancer treatment.Current Genomics 06/2007; 8(4):252-61. DOI:10.2174/138920207781386951 · 2.87 Impact Factor