Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells

Hasegawa, Hiroo; Yamada, Yasuaki; Iha, Hidekatsu; Tsukasaki, Kunihiro; Nagai, Kazuhiro; Atogami, Sunao; Sugahara, Kazuyuki; Tsuruda, Kazuto; Ishizaki, Azumi; Kamihira, Shimeru

doi:10.1038/leu.2009.171

Cited by 64 publications

(74 citation statements)

References 57 publications

(60 reference statements)

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“…43 Therefore, it is of interest to examine the effects of systemic upregulation of p53 on T cell function, as T cell mediated immune surveillance contributes to the control of tumors. In line with a previous study showing that nutlin-3 induces apoptosis in T cell leukemia cell lines, 44 we found that nutlin-3 induced apoptosis in activated T cells, and a corresponding increase in the expression of the pro-apoptotic protein Bax. In addition, and as shown here, nutlin-3 induced a massive increase in p21 and decrease in cMyc, changes that would contribute to cell cycle arrest.…”

Section: Discussionsupporting

confidence: 79%

cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response

et al. 2016

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Activation and proliferation of T cells are tightly regulated during the immune response. We show here that kinetics of proliferation of PHA activated T cells follows the expression of cMyc. Expression of p53 is also elevated and remains high several days after activation. To investigate the role of p53 in activated T cells, its expression was further elevated with nultin-3 treatment, a small molecule that dissociates the E3 ubiquitin protein ligase MDM2 from p53. Concomitantly, cMyc expression and proliferation decreased. At the other end of the cMyc-p53 axis, inhibition of cMyc with 10058-F4 led to down regulation of p53, likely through the lower level of cMyc induced p14ARF, which is also known to dissociate the p53-MDM2 complex. Both compounds induced cell cycle arrest and apoptosis. We conclude that the feedback regulation between cMyc and p53 is important for the T cell homeostasis. We also show that the two compounds modulating p53 and cMyc levels inhibited proliferation without abolishing the cytotoxic function, thus demonstrating the dichotomy between proliferation and cytotoxicity in activated T cells.

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Section: Discussionsupporting

confidence: 79%

cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response

et al. 2016

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“…Also a similar response has been described for T98G cells in response to temozolomide and etoposide [38]. TI-GAR-silenced U87MG and T98G cells showed a significant increase in SA-b-Gal activity, although in other models, such as T-cell leukemia cells, overexpression of TIGAR has been related with a decrease in apoptosis and increase in senescence [6]. Premature senescence has been described as an emerging anticancer response elicited by different stresses, ROS among them [39].…”

Section: Discussionmentioning

confidence: 75%

“…The importance of TIGAR as a regulator of oxidative stress is reflected in its capacity to modulate apoptosis, autophagy and senescence [1,5,6]. ROS regulate several cellular processes, although at higher levels they can induce genotoxic damage and cell death [7].…”

Section: Introductionmentioning

confidence: 99%

TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown results in radiosensitization of glioma cells

Peña‐Rico¹,

Calvo-Vidal²,

Villalonga-Planells³

et al. 2011

Radiotherapy and Oncology

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a b s t r a c tBackground and purpose: The TP53 induced glycolysis and apoptosis regulator (TIGAR) functions to lower fructose-2,6-bisphosphate (Fru-2,6-P 2 ) levels in cells, consequently decreasing glycolysis and leading to the scavenging of reactive oxygen species (ROS), which correlate with a higher resistance to cell death. The decrease in intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic lesions. Given these good prospects of TIGAR for metabolic regulation and p53-response modulation, we analyzed the effects of TIGAR knockdown in U87MG and T98G glioblastoma-derived cell lines. Methods/results: After TIGAR-knockdown in glioblastoma cell lines, different metabolic parameters were assayed, showing an increase in Fru-2,6-P 2 , lactate and ROS levels, with a concomitant decrease in reduced glutathione (GSH) levels. In addition, cell growth was inhibited without evidence of apoptotic or autophagic cell death. In contrast, a clear senescent phenotype was observed. We also found that TIGAR protein levels were increased shortly after irradiation. In addition, avoiding radiotherapy-triggered TIGAR induction by gene silencing resulted in the loss of capacity of glioblastoma cells to form colonies in culture and the delay of DNA repair mechanisms, based in c-H2AX foci, leading cells to undergo morphological changes compatible with a senescent phenotype. Thus, the results obtained raised the possibility to consider TIGAR as a therapeutic target to increase radiotherapy effects. Conclusion: TIGAR abrogation provides a novel adjunctive therapeutic strategy against glial tumors by increasing radiation-induced cell impairment, thus allowing the use of lower radiotherapeutic doses.

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“…The combinatory use of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-related drugs may be one of the most rational choices for Nutlin-3a based treatments. 141 Deguelin, naturally occurring rotenoid, showed a potent anti-proliferative effect on HTLV-1-transformed T-cells. 142 Curcumin, the major yellow pigment in turmeric, targeted Akt cell survival signaling pathway in HTLV-1-infected Tcell lines.…”

Section: ) Other Agents At Pre-clinical Stagementioning

confidence: 99%

Treatment of Adult T-cell Leukemia

Uozumi

2010

J Clin Exp Hematopathol

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Adult T-cell Leukemia (ATL) is an aggressive malignant disease of CD4 + T-cells associated with human T-cell leukemia virus type I (HTLV-I). Prognosis of ATL patients is directly correlated to the subtype of ATL. Treatment of the aggressive forms (acute and lymphoma types) of ATL remains inadequate, as most ATL patients receive conventional chemotherapy without stem cell rescue. At present, LSG15 is the standard chemotherapy for the treatment of aggressive ATL, but the efficacy of LSG15 in most patients is transient. To prolong median survival time, additional therapies for maintenance of complete response (CR) are needed after achieving CR by induction chemotherapy. Improved outcome after allogeneic stem cell transplantation (allo-SCT), despite a high incidence of graft-versus-host disease, has been reported. Thus, allogeneic bone marrow transplantation and allogeneic peripheral blood SCT may have great potential for eradication of HTLV-1 and cure of ATL. Recently, reduced-intensity conditioning stem cell transplantation was also reported to be effective for ATL. Although several issues, including selection criteria for patients and sources of stem cells remain to be resolved, allo-SCT may be considered as a treatment option for patients with aggressive ATL. To evaluate whether allo-SCT is more effective than the standard chemotherapy (LSG15) for aggressive ATL, an upfront phase II clinical trial of JCOG-LSG is now being planned. Novel innovative targeted strategies, such as antiretroviral therapy, arsenic trioxide, nuclear factor-kB inhibitors, proteasome inhibitors, histone deacetylase inhibitors, several monoclonal antibodies including anti-CC chemokine receptor 4, anti-folate, purine nucleotide phosphorylase inhibitor, mTOR (mammalian target of rapamycin) inhibitor, bendamustine, small molecule Bcl-2 inhibitors and Tax-targeted immunotherapy, should be promptly studied in order to develop curative treatments for ATL in the near future. 〔J Clin Exp Hematopathol 50(1) : 9-25, 2010〕

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Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells

Cited by 64 publications

References 57 publications

cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response

cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response

TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown results in radiosensitization of glioma cells

Treatment of Adult T-cell Leukemia

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