scholarly journals Increased p53 Acetylation By SIRT1 Inhibition Is Required for Optimal Activation of p53 Activity and Significantly Enhances the Ability of HDM2 Inhibitors to Target CML LSC

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4521-4521
Author(s):  
Yann Pierre Kevin Duchartre ◽  
Ling Li ◽  
Tinisha McDonald ◽  
YinWei Ho ◽  
Yao-Te Hsieh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Myelogenous Leukemia ◽  
Growth And Survival ◽  
Cycle Arrest ◽  
Cd34 Cells ◽  
Induced Apoptosis ◽  
P53 Target Genes

Abstract BCR-ABL tyrosine kinase inhibitors (TKI) are effective in inducing remissions and prolonging survival in chronic myelogenous leukemia (CML) patients, but do not eliminate leukemia stem cells (LSCs) that are responsible for establishment, maintenance and recurrence of the disease. We have shown that the NAD-dependent SIRT1 deacetylase is overexpressed in CML LSC (Li et al., Cancer Cell, 21:266, 2013). SIRT1 participates in the maintenance, growth and treatment resistance of CML LSC by deacetylation and inhibition of the p53 pathway that regulates cell cycle and apoptosis. Inhibition of SIRT1 using RNAi and the small molecule SIRT1 inhibitor Tenovin-6 (TV-6) inhibits growth and survival of CML LSC by itself and results in enhanced targeting of LSC in combination with TKI treatment. The effects of SIRT1 inhibition are related at least in part to enhanced acetylation of the p53 protein associated with enhanced p53 transcriptional activity. Here we examined the efficacy of an alternative strategy to activate p53, using inhibition of the p53 regulatory protein HDM2, in activating p53 transcriptional activity and inhibiting CML LSC growth and survival compared to SIRT1 inhibition. Nutlin-3 (Nut-3) is a small molecule HDM2 inhibitor that disrupts the p53-HDM2 interaction which has proceeded to clinical trials. Treatment of CML CP CD34+ cells with Nut-3 (1, 2, 5µM) increased expression of the p53 target genes p21 (associated with cell cycle arrest) and NOXA and PIG3 (associated with apoptosis), inhibited proliferation and induced apoptosis to a significantly lesser extent than TV-6 (1, 2 µM) (Nut 5 µM vs TV 2 µM ; p<0.0003) . However, Nutlin-3 enhanced p53 target gene expression and inhibited proliferation and survival of normal CD34+ cells to a similar extent as CML CD34+ cells. This was in contrast to TV-6 which although inhibiting proliferation of both CML and normal CD34+ cells, selectively induced apoptosis in CML compared to normal CD34+ cells. Treatment of CML CD34+ cells with the combination of Nut-3 (2, 5µM) and TV-6 (1µM) significantly increased the expression of p53 target genes (p21, PIG3, NOXA), and enhanced apoptosis of CML CD34+ cells compared to Nut-3 or TV-6 alone. 32D-BCR-ABL cells transduced with lentivirus vectors expressing p53 shRNA demonstrated significantly reduced apoptosis following treatment with the combination of Nut-3 and TV-6 compared to cells expressing control shRNA, indicating that the effects of this treatment are p53 dependent. Our results indicate that enhancement of p53 acetylation by SIRT1 inhibition is required for optimal activation of p53 transcriptional activity and induction of apoptosis in CML LSC. These results further support SIRT1 as a valid therapeutic target in CML, and suggest that addition of SIRT1 inhibitors may significantly enhance the ability of HDM2 inhibitors to eliminate CML LSC. Table 1 : Effects of Nutlin-3, Tenovin-6 or combination on the expression of apoptosis/cell cycle arrest related-genes, apoptosis and proliferation in cord blood and CML CD34+ cells. Figure 1 Figure 1. SEM values ; significance, compared to controls: ***p<0.001. ****p<0.0001. Key words : Chronic Myelogenous Leukemia (CML), hematopoietic stem cells, p53, SIRT1. Disclosures No relevant conflicts of interest to declare.

The Histone Deacetylase Inhibitor LAQ824 Maintains Normal Hematopoietic Progenitor cells (HPC) Associated with Induction of Notch Target Genes and Does Not Eliminate Leukemic HPC in Vitro.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1352-1352
Author(s):  
Kerstin Schwarz ◽  
Oliver Ottmann ◽  
Annette Romanski ◽  
Anja Vogel ◽  
Jeffrey W. Scott ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Progenitor Cells ◽  
Gene Expression Analysis ◽  
Target Genes ◽  
Notch Pathway ◽  
Cycle Arrest ◽  
Cd34 Cells ◽  
20 Nm

Abstract Introduction: Histone deacetylase inhibitors (DACi) have shown promising antileukemic activity by overcoming the differentiation block and inducing apoptosis in AML blasts. Recent data demonstrating enhanced maintenance and functional capacity of normal, but also leukemic hematopoietic progenitor cells (HPC) by the selective class I DACi valproic acid (VPA) have raised concerns about VPA in AML therapy. As more potent pan-DACi have entered clinical trials, we analysed the impact of the hydroxamic acid LAQ824 on phenotype and function of normal and leukemic CD34+ HPC and studied LAQ824- induced gene expression in the most primitive CD34+CD38- population of normal HPC. Methods: Differentiation and proliferation of CD34+ cells of bone marrow of healthy donors and peripheral blood samples of newly diagnosed AML patients were evaluated after one week of culture in presence of SCF, FLT3 ligand, TPO, IL-3 +/− LAQ824. The effect of LAQ824 on gene expression profiles in normal CD34+CD38− cells was assessed in three independent cell samples following incubation with cytokines +/− LAQ824 for 48 hours using Affymetrix GeneChip Human Genome U133 Plus 2.0 and Gene Spring Software. Serial replating of murine Sca1+Lin- HPC was performed in the presence of SCF, G-CSF, GM-CSF, IL-3, IL-6 +/− LAQ824. Results: Treatment of murine Sca1+Lin- HPC with LAQ824 (10 nM) significantly augmented colony numbers (p&lt;0.01; n=3), and supported colony growth after four cycles of replating whereas no colonies developed in its absence beyond the second plating indicating preservation of functionally active multipotent progenitor cells. LAQ824 (10–20 nM) mediated acetylation of histone H3 in human normal and leukemic HPC. In normal HPC, LAQ824 (0–20 nM) lead to a dose-dependent increase in the proportion of CD34+ cells (20% w/o LAQ824 vs. 36% with LAQ824 20nM, p=0.07) and a significant reduction of CD14+ monocytes (18% vs. 3%, p= 0.02; n=3). The total number of CD34+ cells remained stable up to 10 nM and decreased at 20 nM. Gene expression analysis showed, that LAQ824 (20 nM) lead to an at least 3-fold up-regulation of 221 genes in all three HPC samples tested including HDAC11 and the cell cycle inhibitor p21waf1/cip1 known to be induced by most DACi in HPC. We identified several members of the notch pathway such as mastermind-like protein 2 (MAML2, a component of the active notch transcriptional complex) and notch target genes including the transcription factors HES1, HEY1 and HOXA10 and confirmed increase of protein levels by Western blotting. Reduced gene expression of mini-chromosome-maintenance (MCM) protein family members was observed which - in addition to up-regulation of p21 - has previously been associated with notch-mediated cell cycle arrest. To compare the effect of LAQ824 (20 nM) with VPA (150 ng/ml) on leukemic HPC, cells were cultured for one week with or w/o DACi. Of note, LAQ824 resulted in a 0.8-fold reduction of CD34+ leukemic HPC, while VPA expanded this population 2.2-fold compared with cytokine-treated controls (p=0.03; n=12). CFU numbers growing from CD34+ leukemic HPC in presence of LAQ824 did not differ significantly from controls (n=9). Conclusion: LAQ824 seems to diminish, but not eliminate normal as well as leukemic HPC as determined by phenotypic and functional in vitro analyses. Our gene expression analysis suggested an association with coactivator and target genes of the notch pathway and cell cycle arrest-inducing genes. In contrast to VPA, LAQ824 does not seem to support growth of leukemic HPC which may contribute to its more potent antileukemic effect.

scholarly journals FLIP(L) determines p53 induced life or death

2019 ◽  
Author(s):  
Andrea Lees ◽  
Alexander J. McIntyre ◽  
Fiammetta Falcone ◽  
Nyree T. Crawford ◽  
Christopher McCann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Target Genes ◽  
Hdac Inhibitors ◽  
Caspase 8 ◽  
Cycle Arrest ◽  
P53 Activation ◽  
P53 Target Genes ◽  
Mdm2 Inhibitor

AbstractHow p53 differentially activates cell cycle arrest versus cell death remains poorly understood. Here, we demonstrate that upregulation of canonical pro-apoptotic p53 target genes in colon cancer cells imposes a critical dependence on the long splice form of the caspase-8 regulator FLIP (FLIP(L)), which we identify as a direct p53 transcriptional target. Inhibiting FLIP(L) expression with siRNA or Class-I HDAC inhibitors promotes apoptosis in response to p53 activation by the MDM2 inhibitor Nutlin-3A, which otherwise predominantly induces cell-cycle arrest. When FLIP(L) upregulation is inhibited, apoptosis is induced in response to p53 activation via a novel ligand-independent TRAIL-R2/caspase-8 complex, which, by activating BID, induces mitochondrial-mediated apoptosis. Notably, FLIP(L) depletion inhibits p53-induced expression of the cell cycle regulator p21 and enhances p53-mediated upregulation of PUMA, with the latter activating mitochondrial-mediated apoptosis in FLIP(L)-depleted, Nutlin-3A-treated cells lacking TRAIL-R2/caspase-8. Thus, we report two previously undescribed, novel FLIP(L)-dependent mechanisms that determine cell fate following p53 activation.

Foxo Transcription Factor Activity Is Retained in Quiescent Chronic Myeloid Leukaemia Stem Cells and Activated by Tyrosine Kinase Inhibitors to Mediate “induced-quiescence” in More Mature progenitors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 187-187 ◽  
Author(s):  
Daniela Cilloni ◽  
Francesca Pellicano ◽  
Vignir G Helgason ◽  
Cristina Panuzzo ◽  
Francesca Messa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Tyrosine Kinase ◽  
Cell Cycle Arrest ◽  
Progenitor Cells ◽  
Transcriptional Activity ◽  
Kinase Inhibitors ◽  
Akt Pathway ◽  
Cycle Arrest

Abstract Abstract 187 First line therapy for CML involves tyrosine kinase inhibitors (TKIs) which can induce rapid cytogenetic responses in the majority of patients in chronic phase (CP), but do not eliminate BCR-ABL transcripts in the majority, suggesting persistence of residual disease. These findings, together with the rapid kinetics of relapse in patients who discontinue TKIs, suggest the presence of a reservoir of TKI-resistant leukaemic stem cells, although the mechanism for TKI-insensitivity of CML stem cells remains unclear. The FoxO family of transcription factors is mainly regulated by PI3K/Akt induced phosphorylation, resulting in nuclear exclusion and degradation. FOXO activity is implicated in maintaining haemopoietic stem cell (HSC) quiescence. Its transcriptional activity in normal HSC results in cell cycle arrest by expression of p27, p130, p21, down-regulation of Cyclin D and protection from oxidative stress. Cell line studies suggest that FOXOs may play a central role in the anti-proliferative effects of TKIs, but their role in primary CML stem cells has not been previously investigated. Methods: Quiescent CML stem cells were isolated phenotypically (Lin−CD34+38−) by FACS from the total CD34+ stem/progenitor cell population and D-FISH analysis performed to determine the percentage of Ph+ cells. The expression levels of Spred1, FOXO1, FOXO3a, FOXO4 and Cyclin D1 were evaluated by Real-Time-PCR. Protein levels and localization were studied by Western blot, immunofluorescence and FACS. EMSA assay was used to evaluate FOXO3a DNA binding activity. K562 cells were transfected with wt FOXO3a and the constitutively active triple mutant (TM) form of FOXO. After transfection, proliferation and apoptosis were tested using incorporation of H3 thymidine and annexin V detection by FACS, respectively. Results: We found that BCR-ABL, through activation of the PI3K/Akt pathway, induces phosphorylation and cytoplasmic localization of FOXO in CD34+ CML cells, thereby blocking its transcriptional activity as demonstrated by EMSA and by the inhibition of FOXO target genes, including Spred1. Incubation with TKIs decreased phosphorylation and induced re-localization of FOXO to the nucleus in CD34+ CML cells, thus restoring FOXO transcriptional activity. This resulted in decreased levels of Cyclin D1 and reduced ROS. Similar effects and a dramatic reduction of cell proliferation, accompanied by significant apoptosis, were observed by forcing the expression of FOXO3a in K562 through transfection of the TM form, confirming the role of FOXO in inducing cell cycle arrest. Incubation experiments using LY294002, rapamycin and TKIs established that the reactivation of FOXO by TKI is mediated by the PI3K/Akt pathway. Interestingly, we found that phosphorylation of FOXO1, 3a and 4 was higher (i.e. cytoplasmic and inactive) in proliferating CD34+38+ CML cells, as compared to more primitive and quiescent CD34+38−90+ CML cells, although the activity of BCR-ABL, measured by analysis of p-CrKL was found to be similar in both populations, indicating that although present, BCR-ABL was not inducing phosphorylation of FOXO in the quiescent population. In this sense the quiescent CML stem cells resembled normal HSC in terms of FOXO regulation. In conclusion our data indicate that TKIs initiate a process in CML stem and progenitor cells that maintains their quiescence and therefore potential resistance to TKIs themselves. The anti-proliferative activity of TKIs against primary CML CD34+ cells is mediated, at least in part, by the re-activation of FOXO1, 3a and 4. BCR-ABL appears to play a different role in more mature progenitor cells compared to primitive quiescent stem cells, suggesting the possibility of an incomplete activity of BCR-ABL at the stem cell level or alternatively, the possibility that FOXO activity at this level provides the dominant signal responsible for intrinsic quiescence. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The pseudo-caspase FLIP(L) regulates cell fate following p53 activation

2020 ◽  
Vol 117 (30) ◽  
pp. 17808-17819 ◽  
Author(s):  
Andrea Lees ◽  
Alexander J. McIntyre ◽  
Nyree T. Crawford ◽  
Fiammetta Falcone ◽  
Christopher McCann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Target Genes ◽  
Caspase 8 ◽  
Cycle Arrest ◽  
P53 Activation ◽  
Induced Apoptosis

p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53. Genetically or pharmacologically inhibiting expression of FLIP(L) using siRNA or entinostat (a clinically relevant class-I HDAC inhibitor) efficiently promoted apoptosis in colorectal cancer cells in response to Nutlin-3A, which otherwise predominantly induced cell-cycle arrest. Enhanced apoptosis was also observed when entinostat was combined with clinically relevant, p53-activating chemotherapy in vitro, and this translated into enhanced in vivo efficacy. Mechanistically, FLIP(L) inhibited p53-induced apoptosis by blocking activation of caspase-8 by the TRAIL-R2/DR5 death receptor; notably, this activation was not dependent on receptor engagement by its ligand, TRAIL. In the absence of caspase-8, another of its paralogs, caspase-10 (also transcriptionally up-regulated by p53), induced apoptosis in Nutlin-3A-treated, FLIP(L)-depleted cells, albeit to a lesser extent than in caspase-8-proficient cells. FLIP(L) depletion also modulated transcription of canonical p53 target genes, suppressing p53-induced expression of the cell-cycle regulator p21 and enhancing p53-induced up-regulation of proapoptotic PUMA. Thus, even in the absence of caspase-8/10, FLIP(L) silencing promoted p53-induced apoptosis by enhancing PUMA expression. Thus, we report unexpected, therapeutically relevant roles for FLIP(L) in determining cell fate following p53 activation.

Inhibition of Wnt/β-Catenin Signaling by AV65 Treatment Caused Cell Cycle Arrest and Induced Caspase-Independent or -Dependent Apoptosis in CML Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2184-2184 ◽  
Author(s):  
Rina Nagao ◽  
Eishi Ashihara ◽  
Shinya Kimura ◽  
Hisayuki Yao ◽  
Miki Takeuchi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Line ◽  
Cell Lines ◽  
K562 Cells ◽  
S Phase ◽  
G1 Phase ◽  
Cycle Arrest ◽  
Imatinib Resistant ◽  
Induced Apoptosis

Abstract Abstract 2184 Poster Board II-161 Imatinib has dramatically improved the management of CML, but cases of imatinib resistance have been reported. The second-generation ABL tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib overcome imatinib-resistant CML.These agents, however, are ineffective in CML cells harboring T315I mutation and in CML stem cells. Recently, loss of β-catenin has been reported to impair the renewal of CML stem cells (Chao et al, Cancer Cell 2007) and an in vivo study has showed that β-catenin is essential for survival of leukemic stem cells (Hu et al, Leukemia 2009). Thus, we hypothesized that the inhibition of β-catenin signaling may be efficacious in the treatment of CML. We have previously reported that a novel β-catenin inhibitor, AV65, suppresses the growth of imatinib resistant CML cell lines harboring Abl kinase domain mutations including T315I and hypoxia-adaptation (Nagao et al, ASH 2008). We herein examine the cell cycle and apoptotic effects of AV65 on CML cell lines and its therapeutic possibility for CML stem/progenitor cells. We observed that expression of β-catenin is increased 20 to 45-fold in K562, BV173, KT-1, and MYL CML cell lines compared with total bone marrow cells from healthy volunteers. We have previously demonstrated that AV65 induced apoptosis of CML cells. To investigate how AV65 inhibits β-catenin, we next analyzed the effects of AV65 using Western blotting and real time PCR. AV65 suppressed the expression of β-catenin in K562 in a time- and a dose-dependent manner in nuclear and cytosolic fractions as well as whole cell lysates. AV65 did not diminish the transcripts of β-catenin in K562 indicating the depletion of β-catenin due to an inhibition of its accumulation in CML cells. Next we examined the effects of AV65 on cell cycle. The fractions of G1 phase to S phase increased by AV65 treatment. TUNEL/PI staining showed that both K562 and BV173 began to be nicked by AV65 at 30 nM for 12 hours, resulting in the induciton of apoptosis from G1 phase to S phase 24 hours after AV65 treatment (Figure). In real-time PCR analysis, the transcripts of p21, p27, and p57 in CML cell lines increased by AV65 treatment, however, those of p53 were not altered. Taken together, it is suggested that CML cells first arrested from G1 phase to S phase and then induced apoptosis after AV65 treatment. Next we examined the mechanisms of apoptosis by AV65 treatment. AV65 treatment in the presence of Z-VAD did not induce cell death in BV173, indicating that AV65 induced caspase-dependent apoptosis in BV173. In K562 cells however, AV65 induced apoptosis with or without Z-VAD suggesting that AV65 induces apoptosis in CML cell lines in caspase-dependent or -independent pathways. Lastly, we investigated the effects on hypoxia-adapted CML cells. We established hypoxia-adapted K562 cell lines (K562/HA). This cell line shows characteristics of more primitive CML cells, including resistance to serial Abl TKIs and a higher transplantation efficacy compared to the parental K562 cells (Takeuchi, et al. ASH 2008). In Western blotting analysis, K562/HA cell line expressed more β-catenin than its parental K562 cell line. AV65 inhibited the growth of K562/HA at the similar concentration to K562. Taken together, AV65 is effective for primitive CML cells which overexpress β-catenin. This suggests that AV65 has a potential to eradicate CML stem/progenitor cells. In conclusion, AV65 inhibits the accumulation of β-catenin in CML cells and this causes cell cycle arrest from G1 to S phase, resulting in induction of caspase-independent or -dependent apoptosis in CML cells. The inhibition of Wnt/β-catenin signaling has great potential as a novel and attractive therapy for CML. Disclosures: No relevant conflicts of interest to declare.

Without GABP Transcription Factor, BCR-ABL Cannot Transform HSCs to Leukemic Stem Cells Nor Induce Chronic Myelogenous Leukemia in Mice

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 965-965
Author(s):  
Zhongfa Yang ◽  
Cong Peng ◽  
Yaoyu Chen ◽  
Junling Wang ◽  
Xuejun Zhu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Bone Marrow ◽  
Transcription Factor ◽  
Peripheral Blood ◽  
Myeloid Cells ◽  
Myelogenous Leukemia ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem ◽  
Cycle Arrest

Abstract Abstract 965 Chronic Myelogenous Leukemia (CML) is driven by the fusion oncogene, BCR-ABL, which transforms normal hematopoietic stem cells (HSCs) to leukemic stem cells (LSCs). Tyrosine kinase inhibitors, such as imatinib mesylate, control the massive expansion of leukemic cells in most patients with CML, but cannot eradicate CML LSCs. Several genetic pathways have been shown to be critical for the growth and survival of CML LSCs, including signaling molecules, tumor suppressors, and metabolic regulators. However, the role of transcription factors in functional regulation of LSCs in CML has not been widely studied. GA Binding Protein (GABP) is an ets transcription factor that is required for entry of fibroblasts into the cell cycle, and expression of Gabpa (the DNA-binding component of the complex), alone, was sufficient to induce quiescent, serum-starved cells to enter the cell cycle. Thus, Gabp is both necessary and sufficient for cell cycle entry. Conditional deletion of Gabpa in mouse bone marrow decreased hematopoietic progenitor cells more than 100-fold, but hematopoietic stem cells (HSCs) were relatively preserved. Gabpα null HSCs exhibited significant cell cycle arrest. We sought to determine if the cell cycle arrest caused by Gabpa loss could impair development of CML cells in a mouse model. We used retroviral infection of bone marrow from 5-FU-treated mice (to enrich for stem and progenitor cells) to generate a rapidly fatal CML-like syndrome in mice. Bone marrow from mice with loxP-flanked (floxed) Gabpa and wild type control mice was infected with a retrovirus that co-expresses BCR-ABL, Cre recombinase, and green fluorescent protein (GFP). As expected, transplantation into recipient mice of control mouse bone marrow infected with BCR-ABL-Cre-GFP retrovirus caused a rapidly fatal myeloproliferative neoplasm, with a median survival of approximately three weeks; mice died with massive infiltration of GFP+ myeloid cells in peripheral blood cell, spleen, bone marrow, and other organs. In floxed Gabpa bone marrow, the retrovirus deleted floxed Gabpa in cells that express the BCR-ABL fusion oncogene, and these cells were identifiable based on GFP expression. Transplantation of floxed Gabpa bone marrow infected with BCR-ABL-Cre-GFP retrovirus failed to induce CML during six months of observation. Importantly, GFP+ peripheral blood granulocytes were observed for at least 6 months after transplantation; these CD11b+, Gr1+ cells continued to express BCR-ABL and were shown to be Gabpa null. These results indicate that the lack of Gabpa severely impaired the function of LSCs. In addition, secondary transplantation of bone marrow from these mice again demonstrated the presence of BCR-ABL-expressing peripheral blood myeloid cells. We conclude that Gabp transcription factor is required for the transformation of HSCs to LSCs by BCR-ABL. Furthermore, the persistence of BCR-ABL-expressing myeloid cells without the development of leukemia provides a unique model that permits analysis of the biological properties of BCR-ABL in vivo. The continued generation of BCR-ABL-expressing cells without CML development is unprecedented, and represents a unique model of leukemia tumor suppression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Jellyfish extract induces apoptotic cell death through the p38 pathway and cell cycle arrest in chronic myelogenous leukemia K562 cells

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e2895 ◽  
Author(s):  
Sun-Hyung Ha ◽  
Fansi Jin ◽  
Choong-Hwan Kwak ◽  
Fukushi Abekura ◽  
Jun-Young Park ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Chronic Myelogenous Leukemia ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
G1 Phase ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Induced Apoptosis ◽  
Cancer Activity

Jellyfish species are widely distributed in the world’s oceans, and their population is rapidly increasing. Jellyfish extracts have several biological functions, such as cytotoxic, anti-microbial, and antioxidant activities in cells and organisms. However, the anti-cancer effect of Jellyfish extract has not yet been examined. We used chronic myelogenous leukemia K562 cells to evaluate the mechanisms of anti-cancer activity of hexane extracts from Nomura’s jellyfish in vitro. In this study, jellyfish are subjected to hexane extraction, and the extract is shown to have an anticancer effect on chronic myelogenous leukemia K562 cells. Interestingly, the present results show that jellyfish hexane extract (Jellyfish-HE) induces apoptosis in a dose- and time-dependent manner. To identify the mechanism(s) underlying Jellyfish-HE-induced apoptosis in K562 cells, we examined the effects of Jellyfish-HE on activation of caspase and mitogen-activated protein kinases (MAPKs), which are responsible for cell cycle progression. Induction of apoptosis by Jellyfish-HE occurred through the activation of caspases-3,-8 and -9 and phosphorylation of p38. Jellyfish-HE-induced apoptosis was blocked by a caspase inhibitor, Z-VAD. Moreover, during apoptosis in K562 cells, p38 MAPK was inhibited by pretreatment with SB203580, an inhibitor of p38. SB203580 blocked jellyfish-HE-induced apoptosis. Additionally, Jellyfish-HE markedly arrests the cell cycle in the G0/G1 phase. Therefore, taken together, the results imply that the anti-cancer activity of Jellyfish-HE may be mediated apoptosis by induction of caspases and activation of MAPK, especially phosphorylation of p38, and cell cycle arrest at the Go/G1 phase in K562 cells.

Sign in / Sign up

Export Citation Format

Share Document