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1.
Oncogene ; 35(8): 977-89, 2016 Feb 25.
Article in English | MEDLINE | ID: mdl-25961931

ABSTRACT

Many drugs currently used in chemotherapy work by hindering the process of ribosome biogenesis. In tumors with functional p53, the inhibition of ribosome biogenesis may contribute to the efficacy of this treatment by inducing p53 stabilization. As the level of stabilized p53 is critical for the induction of cytotoxic effects, it seems useful to highlight those cancer cell characteristics that can predict the degree of p53 stabilization following the treatment with inhibitors of ribosome biogenesis. In the present study we exposed a series of p53 wild-type human cancer cell lines to drugs such as actinomycin D (ActD), doxorubicin, 5-fluorouracil and CX-5461, which hinder ribosomal RNA (rRNA) synthesis. We found that the amount of stabilized p53 was directly related to the level of ribosome biogenesis in cells before the drug treatment. This was due to different levels of inactivation of the ribosomal proteins-MDM2 pathway of p53 digestion. Inhibition of rRNA synthesis always caused cell cycle arrest, independent of the ribosome biogenesis rate of the cells, whereas apoptosis occurred only in cells with a high rDNA transcription rate. The level of p53 stabilization induced by drugs acting in different ways from the inhibition of ribosome biogenesis, such as hydroxyurea (HU) and nutlin-3, was independent of the level of ribosome biogenesis in cells and always lower than that occurring after the inhibition of rRNA synthesis. Interestingly, in cells with a low ribosome biogenesis rate, the combined treatment with ActD and HU exerted an additive effect on p53 stabilization. These results indicated that (i) drugs inhibiting ribosome biogenesis may be highly effective in p53 wild-type cancers with a high ribosome biogenesis rate, as they induce apoptotic cell death, and (ii) the combination of drugs capable of stabilizing p53 through different mechanisms may be useful for treating cancers with a low ribosome biogenesis rate.


Subject(s)
Antineoplastic Agents/pharmacology , Organelle Biogenesis , RNA, Ribosomal/drug effects , Ribosomes/drug effects , Tumor Suppressor Protein p53/metabolism , Apoptosis , Humans , Protein Stability/drug effects , RNA, Ribosomal/biosynthesis , Ribosomes/metabolism , Transcription, Genetic/drug effects , Tumor Cells, Cultured
2.
Oncogene ; 33(35): 4396-406, 2014 Aug 28.
Article in English | MEDLINE | ID: mdl-24531714

ABSTRACT

Chronic inflammation is an established risk factor for the onset of cancer, and the inflammatory cytokine IL-6 has a role in tumorigenesis by enhancing proliferation and hindering apoptosis. As factors stimulating proliferation also downregulate p53 expression by enhancing ribosome biogenesis, we hypothesized that IL-6 may cause similar changes in inflamed tissues, thus activating a mechanism that favors neoplastic transformation. Here, we showed that IL-6 downregulated the expression and activity of p53 in transformed and untransformed human cell lines. This was the consequence of IL-6-dependent stimulation of c-MYC mRNA translation, which was responsible for the upregulation of rRNA transcription. The enhanced rRNA transcription stimulated the MDM2-mediated proteasomal degradation of p53, by reducing the availability of ribosome proteins for MDM2 binding. The p53 downregulation induced the acquisition of cellular phenotypic changes characteristic of epithelial-mesenchymal transition, such as a reduced level of E-cadherin expression, increased cell invasiveness and a decreased response to cytotoxic stresses. We found that these changes also occurred in colon epithelial cells of patients with ulcerative colitis, a very representative example of chronic inflammation at high risk for tumor development. Histochemical and immunohistochemical analysis of colon biopsy samples showed an upregulation of ribosome biogenesis, a reduced expression of p53, together with a focal reduction or absence of E-cadherin expression in chronic colitis in comparison with normal mucosa samples. These changes disappeared after treatment with anti-inflammatory drugs. Taken together, the present results highlight a new mechanism that may link chronic inflammation to cancer, based on p53 downregulation, which is activated by the enhancement of rRNA transcription upon IL-6 exposure.


Subject(s)
Colitis, Ulcerative/metabolism , Colonic Neoplasms/metabolism , Epithelial-Mesenchymal Transition/drug effects , Interleukin-6/pharmacology , RNA, Ribosomal/genetics , Tumor Suppressor Protein p53/metabolism , Adult , Anti-Inflammatory Agents/therapeutic use , Cadherins/metabolism , Cell Line, Tumor , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/pathology , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Female , Gene Expression Regulation/drug effects , Hep G2 Cells , Humans , Male , Middle Aged , Proto-Oncogene Proteins c-mdm2/metabolism , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , RNA, Ribosomal/metabolism , Ribosomal Proteins/metabolism , Ribosomes/genetics , Ribosomes/metabolism , Signal Transduction , Tumor Suppressor Protein p53/genetics
3.
Oncogene ; 30(29): 3274-88, 2011 Jul 21.
Article in English | MEDLINE | ID: mdl-21399665

ABSTRACT

Data on the relationship between ribosome biogenesis and p53 function indicate that the tumour suppressor can be activated by either nucleolar disruption or ribosomal protein defects. However, there is increasing evidence that the induction of p53 does not always require these severe cellular changes, and data are still lacking on a possible role of ribosome biogenesis in the downregulation of p53. Here, we studied the effect of the up- and downregulation of the rRNA transcription rate on p53 induction in mammalian cells. We found that a downregulation of rRNA synthesis, induced by silencing the POLR1A gene coding for the RNA polymerase I catalytic subunit, stabilised p53 without altering the nucleolar integrity in human cancer cells. p53 stabilisation was due to the inactivation of the MDM2-mediated p53 degradation by the binding of ribosomal proteins no longer used for ribosome building. p53 stabilisation did not occur when rRNA synthesis downregulation was associated with a contemporary reduction of protein synthesis. Furthermore, we demonstrated that in three different experimental models characterised by an upregulation of rRNA synthesis, cancer cells treated with insulin or exposed to the insulin-like growth factor 1, rat liver stimulated by cortisol and regenerating rat liver after partial hepatectomy, the p53 protein level was reduced due to a lowered ribosomal protein availability for MDM2 binding. It is worth noting that the upregulation of rRNA synthesis was responsible for a decreased p53-mediated response to cytotoxic stresses. These findings demonstrated that the balance between rRNA and ribosomal protein synthesis controls the function of p53 in mammalian cells, that p53 can be induced without the occurrence of severe changes of the cellular components controlling ribosome biogenesis, and that conditions characterised by an upregulated rRNA synthesis are associated with a reduced p53 response.


Subject(s)
Down-Regulation , RNA, Ribosomal/biosynthesis , Ribosomal Proteins/biosynthesis , Tumor Suppressor Protein p53/metabolism , Up-Regulation , Animals , Cell Line, Tumor , Cell Nucleolus/metabolism , Gene Silencing , Humans , Hydrolysis , Proteasome Endopeptidase Complex/metabolism , RNA, Ribosomal/genetics , Rats , Ribosomal Proteins/genetics , Tumor Suppressor Protein p53/genetics
4.
Ann Oncol ; 20(11): 1818-23, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19556322

ABSTRACT

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive disease, nevertheless exhibiting a high response rate to chemotherapy. Since the retinoblastoma protein (pRb) loss confers a high sensitivity to chemotherapy regimens, we evaluated the prevalence of pRb loss in TNBCs and its relevance on the clinical outcome of patients treated with adjuvant chemotherapy. PATIENTS AND METHODS: pRb status was prospectively evaluated by immunocytochemistry in 518 consecutive patients with complete receptor information. The predictive value of pRb status in TNBCs was determined according to the adjuvant therapeutic treatments. RESULTS: Fifty-three tumors were identified as TNBCs. The prevalence of pRb loss was significantly higher in TNBCs than in the other cancer subtypes. All patients with TNBCs lacking pRb and treated with systemic chemotherapy (cyclophosphamide, methotrexate and 5-fluorouracil) were disease free at a medium follow-up time of 109 months, whereas the clinical outcome of those expressing pRb was significantly poorer (P = 0.008). Analysis of disease-free survival including the established anatomo-clinical prognostic parameters indicated pRb loss as the only significant predictive factor. CONCLUSIONS: pRb loss is much more frequent in TNBCs than in the other breast cancer subtypes. Patients with TNBCs lacking pRb had a very favorable clinical outcome if treated with conventional adjuvant chemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Retinoblastoma Protein/biosynthesis , Adult , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Cyclophosphamide/administration & dosage , Disease-Free Survival , Drug Resistance, Neoplasm , Female , Fluorouracil/administration & dosage , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Methotrexate/administration & dosage , Middle Aged , Neoplasm Staging , Prevalence , Prognosis , Receptor, ErbB-2/biosynthesis , Receptors, Estrogen/biosynthesis , Receptors, Progesterone/biosynthesis
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