TAp63α Mediates Chemotherapeutic Agent-Induced Apoptosis in Human Bone Marrow Mesenchymal Stem Cells
Institute of Basic Medical Sciences and School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.Stem cells and development (Impact Factor: 3.73). 12/2010; 20(8):1319-26. DOI: 10.1089/scd.2010.0329
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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- "pression , independent of apoptosis induction . Apoptosis induced by cisplatin or etoposide in MSCs is accompanied by expression of TAp63α , a subtype of p63 , highly similar to p53 . Downreg - ulation of TAp63α does not influence the phenotype , proliferation ca - pacity , and differentiation potential of MSCs , but markedly decreases apoptosis ( Lu et al . , 2011 ) . Overexpression of p73 , which is also a mem - ber of the p53 family , in human bone marrow MSCs significantly en - hances sensitivity to cisplatin . Treatment of p73 overexpressing cells with cisplatin results in co - activation of the pro - apoptotic factors Bax and p21 , suggesting that p73α is an important determinant of human bo"
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.
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- "Chemotherapeutic agents induce TAp63 expression, which subsequently causes apoptosis by directly activating pro-apoptotic genes CD95, Bcl-2-family members such as bax and BCL2L11 as well as Apaf1 . Consequently, inhibition of TAp63 function, which causes reduced apoptosis, leads to drug resistance in various cancers [55,58–60]. "
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.
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ABSTRACT: p53 mutations, occurring in two-thirds of all human cancers, confer a gain of function phenotype, including the ability to form metastasis, the determining feature in the prognosis of most human cancer. This effect seems mediated at least partially by its ability to physically interact with p63, thus affecting a cell invasion pathway, and accordingly, p63 is deregulated in human cancers. In addition, p63, as an 'epithelial organizer', directly impinges on epidermal mesenchimal transition, stemness, senescence, cell death and cell cycle arrest, all determinant in cancer, and thus p63 affects chemosensitivity and chemoresistance. This demonstrates an important role for p63 in cancer development and its progression, and the aim of this review is to set this new evidence that links p63 to metastasis within the context of the long conserved other functions of p63.
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