ABSTRACT
BACKGROUND: The increasing usage of statins (the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) has revealed a number of unexpected beneficial effects, including a reduction in cancer risk. METHODS: We investigated the direct anticancer effects of different statins approved for clinical use on human breast and brain cancer cells. We also explored the effects of statins on cancer cells using in silico simulations. RESULTS: In vitro studies showed that cerivastatin, pitavastatin, and fluvastatin were the most potent anti-proliferative, autophagy inducing agents in human cancer cells including stem cell-like primary glioblastoma cell lines. Consistently, pitavastatin was more effective than fluvastatin in inhibiting U87 tumour growth in vivo. Intraperitoneal injection was much better than oral administration in delaying glioblastoma growth. Following statin treatment, tumour cells were rescued by adding mevalonate and geranylgeranyl pyrophosphate. Knockdown of geranylgeranyl pyrophosphate synthetase-1 also induced strong cell autophagy and cell death in vitro and reduced U87 tumour growth in vivo. These data demonstrate that statins main effect is via targeting the mevalonate synthesis pathway in tumour cells. CONCLUSIONS: Our study demonstrates the potent anticancer effects of statins. These safe and well-tolerated drugs need to be further investigated as cancer chemotherapeutics in comprehensive clinical studies.
Subject(s)
Antineoplastic Agents/pharmacology , Mevalonic Acid/metabolism , Animals , Autophagy/drug effects , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Computer Simulation , Disease Models, Animal , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , In Vitro Techniques , Mice , Mice, NudeABSTRACT
The E2F family of transcription factors regulates the expression of a number of genes whose products are involved in cell cycle control, DNA replication and apoptosis. We show here that E2F-1 binds in vivo the promoters of ASPP1 and ASPP2 genes, two activators of p53-mediated apoptosis, E2F-1, E2F-2 and E2F-3 all activate the isolated ASPP1 and ASPP2 promoters. Overexpression or deregulation of E2F-1 increased the expression levels of ASPP1 and ASPP2 mRNA and proteins. The identification of ASPP1 and ASPP2 genes as transcriptional targets of E2F provides another mechanism by which E2F cooperates with p53 to induce apoptosis.
Subject(s)
Carrier Proteins/genetics , Cell Cycle Proteins/metabolism , DNA-Binding Proteins/metabolism , Transcription Factors/metabolism , Adaptor Proteins, Signal Transducing , Apoptosis Regulatory Proteins , Base Sequence , Carrier Proteins/biosynthesis , E2F Transcription Factors , E2F1 Transcription Factor , E2F2 Transcription Factor , E2F3 Transcription Factor , Humans , Molecular Sequence Data , Promoter Regions, Genetic , RNA, Messenger/metabolismABSTRACT
Covalent modification of the promyelocytic leukaemia protein (PML) by SUMO-1 is a prerequisite for the assembly of nuclear bodies (NBs), subnuclear structures disrupted in various human diseases and linked to transcriptional and growth control. Here we demonstrate that p53 is recruited into NBs by a specific PML isoform (PML3) or by coexpression of SUMO-1 and hUbc9. NB targeting depends on the direct association of p53, through its core domain, with a C-terminal region of PML3. The relocalization of p53 into NBs enhances p53 transactivation in a promoter-specific manner and affects cell survival. Our results indicate the existence of a cross-talk between PML- and p53-dependent growth suppression pathways, implying an important role for NBs and their resident proteins as modulators of p53 functions.
Subject(s)
Neoplasm Proteins/metabolism , Nuclear Proteins , Transcription Factors/metabolism , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Conjugating Enzymes , Biological Transport, Active , Cell Nucleus/metabolism , Cell Survival , Humans , Ligases/genetics , Ligases/metabolism , Neoplasm Proteins/genetics , Promyelocytic Leukemia Protein , Protein Binding , Protein Isoforms/genetics , Protein Isoforms/metabolism , SUMO-1 Protein , Transcription Factors/genetics , Transcription, Genetic , Tumor Cells, Cultured , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins , Ubiquitins/genetics , Ubiquitins/metabolismABSTRACT
Control of cell growth and division by the p53 tumor suppressor protein requires its abilities to transactivate and repress specific target genes and to associate in complex with other proteins. Here we demonstrate that p53 binds to the E1A-regulated transcription factor p120E4F, a transcriptional repressor of the adenovirus E4 promoter. The interaction involves carboxy-terminal half of p120E4F and sequences located at the end of the sequence-specific DNA-binding domain of p53. Ectopic expression of p120E4F leads to a block of cell proliferation in several human and murine cell lines and this effect requires the association with wild-type (wt) p53. Although p120E4F can also bind to mutant p53, the growth suppression induced by overexpression of the protein is severely reduced in a cell line that contains mutant p53. These data suggest that p120E4F may represent an important element within the complex network of p53 checkpoint functions.
Subject(s)
Adenovirus E4 Proteins/physiology , Growth Inhibitors/physiology , Tumor Suppressor Protein p53/physiology , 3T3 Cells , Adenovirus E4 Proteins/biosynthesis , Adenovirus E4 Proteins/genetics , Adenovirus E4 Proteins/isolation & purification , Amino Acids/physiology , Animals , Growth Inhibitors/genetics , Humans , Mice , Mice, Inbred BALB C , Peptide Fragments/physiology , Protein Binding/genetics , Transcriptional Activation , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Zinc Fingers/genetics , Zinc Fingers/physiologyABSTRACT
The growth-suppressive properties of p53 are controlled by posttranslational modifications and by regulation of its turnover rate. Here we show that p53 can be modified in vitro and in vivo by conjugation to the small ubiquitin-like protein SUMO-1. A lysine residue at amino acid position 386 of p53 is required for this previously undescribed modification, strongly suggesting that this lysine residue serves as the major attachment site for SUMO-1. Unlike ubiquitin, attachment of SUMO-1 does not appear to target proteins for rapid degradation but rather, has been proposed to change the ability of the modified protein to interact with other cellular proteins. Accordingly, we provide evidence that conjugation of SUMO-1 to wild-type p53 results in an increased transactivation ability of p53. We suggest that posttranslational modification of p53 by SUMO-1 conjugation provides a novel mechanism to regulate p53 activity.
