Wild-type (wt) p53-induced phosphatase 1 (Wip1), encoded by the protein phosphatase, Mg 2+ /Mn 2+ dependent 1D (PPM1D) gene, is a serine/threonine phosphatase induced upon genotoxic stress in a p53-dependent manner. Wip1/PPM1D is frequently overexpressed, amplified and mutated in human solid tumors harboring wt p53 and is thus currently recognized as an oncogene. Oncogenic Wip1 dampens cellular stress responses, such as cell cycle checkpoints, apoptosis and senescence, and consequently increases resistance to anticancer therapeutics. Targeting Wip1 has emerged as a therapeutic strategy for tumors harboring wt p53. However, little is known about the efficacy of Wip1-targeted therapies in tumors lacking p53. The present study aimed to investigate the potential role of oncogenic Wip1 in p53 mutant (mt) Jurkat cells. In the present study, it was demonstrated that p53 mt Jurkat cells exhibited PPM1D/Wip1 gene amplification and expressed relatively high levels of Wip1, as confirmed by gene copy number and RNA expression analysis. In addition, Jurkat cells underwent G2 cell cycle arrest, apoptotic cell death and senescence in response to etoposide and doxorubicin, although the phosphorylation levels of DNA damage response (DDR) elements, including ataxia-telangiectasia mutated, ataxia-telangiestasia and Rad3-related, checkpoint kinase (Chk)1 and Chk2 were significantly low. Accordingly, the targeting of Wip1 phosphatase by RNA interference increased the phosphorylation of DDR elements, but decreased the rate of apoptosis in response to etoposide or doxorubicin in Jurkat cells. The induction of senescence or cell cycle arrest was not affected by the knockdown of Wip1. The results suggest that increased Wip1 expression enhances the apoptotic sensitivity of Jurkat cells in response to chemotherapeutic agents by attenuating DDR signaling. The present study highlights the possible pro-apoptotic role of Wip1 in a p53 mt T-cell acute lymphoblastic leukemia cell line. The data suggest the careful consideration of future treatment strategies aiming to manipulate or target Wip1 in human cancers lacking p53.
Doxorubicin (DOX) is a potent chemotherapeutic agent and has toxic effects on various organs, including the liver. In the current study, we aimed to investigate the effects of bone‐marrow‐derived mesenchymal stem cell (BM‐MSC) administration on DOX‐induced hepatotoxicity in rats. 24 Wistar‐albino rats were divided into three groups: Control, DOX, and DOX+MSC. DOX (20 mg/kg) was administered to the DOX group. In the DOX + MSC group, BM‐MSCs (2 × 106) were given through the tail vein following DOX administration. DOX administration led to significant structural liver injury. Besides this, oxidative balance in the liver was impaired following DOX administration. DOX administration also led to an increase in apoptotic cell death in the liver. Structural and oxidative changes were significantly alleviated with the administration of BM‐MSCs. Furthermore, BM‐MSC administration suppressed excessive apoptotic cell death. Our findings revealed that BM‐MSC administration may alleviate DOX‐induced liver injury via improving the oxidative status and limiting apoptotic cell death in the liver tissue.
Chemotherapeutic agents that cause DNA damage also induce cellular senescence known as therapy-induced senescence (TIS).Cells undergoing senescence may exert detrimental effects by promoting tumor progression in healthy cells or supporting metastases in cancer cells due to "senesence-associated secretory phenotype" (SASP), involving secretion of chemokines, cytokines, metalloproteinases, and growth factors. Death receptors belong to the tumor necrosis factor receptor superfamily and implicated in induction of apoptosis via activation of extrinsic pathway. The most recognized death receptors are FAS (CD95), TNFR1 and TRAIL-R1 / 2 (DR4-DR5) etc. and capable of directly inducing apoptosis in the cell. In this study we aimed to investigate the expression of cell death receptors in response to TIS of breast cancer cells for their potential use in elimination of senescent cells.Doxorubicin and etoposide were used to induce senescence selectively in MCF7 breast cancer cell line. Senescence induction was confirmed by β-galactosidase staining and cell cycle analysis. Activations of p53, p21, and γ-H2AX and expression levels of cell death receptors (FAS (CD95), TNFR1-2 and DR5 were tested by western blot analysis. Apoptosis was measured by Annexin V/7AAD analysis.Here, we show that chemotherapy agents etoposide and doxorubicin induced senescence by arresting MCF-12A and MCF-7 cells in G1 and G2/M phases of cell cycle, respectively. Induction of senescence is confirmed by SA-β-gal staining and by activation of -H2AX, p53 and p21 proteins. Neither etoposide nor doxorubicin induced significant apoptosis in MCF12A or MCF-7 cells.Importantly, TIS increased the protein levels of TNFR1, TNFR2 and DR5 receptors selectively in MCF-7 cells but not in MCF-12A cells. These data suggest that chemotherapy agents induce senescence increased the expression of death receptors in breast cancer cell line MCF-7 thus provide a basis for further investigation of death receptor mediated targeting of senescent cells as potential therapeutic strategy.
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