Exploiting the p53 pathway for the diagnosis and therapy of human cancer.
ABSTRACT After 26 years of research and the publication of 38,000 papers, our knowledge of the p53 human tumor suppressor protein is impressive. Over half of all human cancers have mutations in the p53 gene, and the p53 pathway in animal models dramatically regulates the cellular response to ionizing radiation and chemotherapeutic drugs. The ability to translate this knowledge to patient benefit is, however, still in its infancy. The many approaches to determining the status of the p53 pathway in human tumor biopsy samples and the attempts to develop p53-selective therapies are described. A great deal of our knowledge of the p53 system remains incomplete, and the issue of how to best conduct translational research in cancer is debated using the difficulties around the p53 system as an example. The need for a more unified and coordinated approach to critical technological developments and clinical trial protocols is discussed.
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ABSTRACT: Cancer cell killing might be achieved by the combined use of available drugs. Statins are major anti-hypercholesterolemia drugs, which also trigger apoptosis of many cancer cell types, while docetaxel is a potent microtubule-stabilising agent. Here, we looked at the combined effects of lovastatin and docetaxel in cancer cells. Whole transcriptome microarrays in HGT-1 gastric cancer cells demonstrated that lovastatin strongly suppressed expression of genes involved in cell division, while docetaxel had very little transcriptional effects. Both drugs triggered apoptosis, and their combination was more than additive. A marked rise in the cell-cycle inhibitor p21, together with reduction of aurora kinases A and B, cyclins B1 and D1 proteins was induced by lovastatin alone or in combination with docetaxel. The drug treatments induced the proteolytic cleavage of procaspase-3, a drop of the anti-apoptotic Mcl-1 protein, Poly-ADP-Ribose Polymerase and Bax. Strikingly, docetaxel-resistant HGT-1 cell derivatives overexpressing the MDR-1 gene were much more sensitive to lovastatin than docetaxel-sensitive cells. These results suggest that the association of lovastatin and docetaxel, or lovastatin alone, shows promise as plausible anticancer strategies, either as a direct therapeutic approach or following acquired P-glycoprotein-dependent resistance.British Journal of Cancer 02/2012; 106(4):685-92. DOI:10.1038/bjc.2012.6 · 4.82 Impact Factor
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ABSTRACT: The p53 tumor suppressor pathway is central both in reducing cancer frequency in vertebrates and in mediating the response of commonly used cancer therapies. This article aims to summarize and discuss a large body of evidence suggesting that the p53 pathway harbors functional inherited single-nucleotide polymorphisms (SNPs) that affect p53 signaling in cells, resulting in differences in cancer risk and clinical outcome in humans. The insights gained through these studies into how the functional p53 pathway SNPs could help in the tailoring of cancer therapies to the individual are discussed. Moreover, recent work is discussed that suggests that many more functional p53 pathway SNPs are yet to be fully characterized and that a thorough analysis of the functional human genetics of this important tumor suppressor pathway is required.Cold Spring Harbor perspectives in biology 05/2010; 2(5):a001032. DOI:10.1101/cshperspect.a001032 · 8.23 Impact Factor
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ABSTRACT: The tumor suppressor p53 is a transcription factor that responds to cellular stresses by initiating cell cycle arrest or apoptosis. One transcriptional target of p53 is Mdm2, an E3 ubiquitin ligase that interacts with p53 to promote its proteasomal degradation in a negative feedback regulatory loop. Here we show that the wild-type p53-induced phosphatase 1 (Wip1), or PPM1D, downregulates p53 protein levels by stabilizing Mdm2 and facilitating its access to p53. Wip1 interacts with and dephosphorylates Mdm2 at serine 395, a site phosphorylated by the ATM kinase. Dephosphorylated Mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation. Thus, Wip1 acts as a gatekeeper in the Mdm2-p53 regulatory loop by stabilizing Mdm2 and promoting Mdm2-mediated proteolysis of p53.Cancer Cell 11/2007; 12(4):342-54. DOI:10.1016/j.ccr.2007.08.033 · 23.89 Impact Factor