TAp63α mediates chemotherapeutic agent-induced apoptosis in human bone marrow mesenchymal stem cells.
ABSTRACT Human bone marrow-derived mesenchymal stem cells (MSCs) are currently widely used in cell therapy and tissue engineering. In vitro experiments have demonstrated that apoptosis of MSCs can be induced by hypoxia, serum deprivation, and chemotherapeutic agents, and the process is p53 independent. In this study, we investigated the role of p63 (a member of p53 family) in the regulation of apoptosis of MSCs. TAp63α, a subtype of p63, is highly similar to p53 and plays a crucial role in apoptosis. In vitro exposure of MSCs to either cisplatin or etoposide resulted in an increased TAp63α expression, which was time and dose dependent. Interference of TAp63α led to drug resistance and decreased apoptosis, accompanied by reduced expression of Bax, poly(ADP-ribose) polymerase, and caspase-3. However, downregulation of TAp63α did not influence the phenotype, proliferation capacity, and differentiation potential of MSCs. These results indicate that downregulation of TAp63α in MSCs is an attractive strategy to protect against apoptosis when MSCs are used to support hematopoiesis during bone marrow transplantation.
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ABSTRACT: p63 is a transcriptional factor belonging to p53 family of genes. Beside the role in cancer, partially shared with p53 and the other member p73, p63 also plays exclusive roles in development and homeostasis of ectodermal/epidermal-related organs. Here we show that p63 transcriptionally controls the expression of the matrix metallopeptidase 13 (MMP13). p63 binds a p53-like responsive element in the human promoter of MMP13, thus promoting the activation of its transcription. The catalytic activity of MMP13 is required in high invasion capacity of metastatic cancer cells, however, although p63 and MMP13 expression correlates in cancer patients, their co-expression does not predict cancer patient survival. Our results demonstrate that p63 directly controls MMP13 expression.Oncotarget 02/2014; 5(5). · 6.63 Impact Factor
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ABSTRACT: Since cancer is one of the leading causes of death worldwide, there is an urgent need to find better treatments. Currently, the use of chemotherapeutics remains the predominant option for cancer therapy. However, one of the major obstacles for successful cancer therapy using these chemotherapeutics is that patients often do not respond or eventually develop resistance after initial treatment. Therefore identification of genes involved in chemotherapeutic response is critical for predicting tumour response and treating drug-resistant cancer patients. A group of genes commonly lost or inactivated are tumour suppressor genes, which can promote the initiation and progression of cancer through regulation of various biological processes such as cell proliferation, cell death and cell migration/invasion. Recently, mounting evidence suggests that these tumour suppressor genes also play a very important role in the response of cancers to a variety of chemotherapeutic drugs. In the present review, we will provide a comprehensive overview on how major tumour suppressor genes [Rb (retinoblastoma), p53 family, cyclin-dependent kinase inhibitors, BRCA1 (breast-cancer susceptibility gene 1), PTEN (phosphatase and tensin homologue deleted on chromosome 10), Hippo pathway, etc.] are involved in chemotherapeutic drug response and discuss their applications in predicting the clinical outcome of chemotherapy for cancer patients. We also propose that tumour suppressor genes are critical chemotherapeutic targets for the successful treatment of drug-resistant cancer patients in future applications.Bioscience Reports 08/2012; 32(4):361-74. DOI:10.1042/BSR20110125 · 2.85 Impact Factor
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ABSTRACT: Multipotent mesenchymal stromal cells (MSCs) are involved in the organization and maintenance of tissue integrity. MSCs have also attracted attention as a promising tool for cell therapy and regenerative medicine. However, their usage is limited due to cell impairment induced by an extremely harsh microenvironment during transplantation ex vivo. The microenvironment of MSCs in tissue depots is characterized by rather low oxygen consumption, demonstrating that MSCs might be quite resistant to oxygen limitation. However, accumulated data revealed that the response of MSCs to hypoxic conditions are rather controversial, demonstrating both damaging and ameliorating effects. Here, we make an attempt to summarize recent knowledge on the survival of MSCs under low oxygen conditions of various duration and severity, and to elucidate the mechanisms of MSC resistance/sensitivity to hypoxic impact.Mitochondrion 11/2014; 19. DOI:10.1016/j.mito.2014.07.005 · 3.52 Impact Factor