All-trans-retinoic acid increases cytosine arabinoside cytotoxicity in HL-60 human leukemia cells in spite of decreased cellular ara-CTP accumulation

Freund, Anna; Lanvers, Claudia; Gescher, Andreas J.; Hohenlöchter, Barbara; Jürgens, H.; Boos, Joachim

doi:10.1023/a:1008365714942

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…The cells were then treated with AraC, a DNA-damaging agent with IC 50 value between 5 and 10M in leukemic cells. 35 To monitor for AraC-induced onset of apoptosis, we measured the cleavage of caspase-7 (C-7) and poly(ADP-ribose) polymerase (PARP) as indicators for their activation and onset of apoptosis. In NB4 cells transfected with empty vector, thus only expressing endogenous level of GRP78, we observed an increase in the level of cleaved C-7 and PARP in an AraC-dosagedependent manner ( Figure 6A).…”

Section: Knockdown Of Grp78 In Human Leukemic Cells Enhances Arac-indmentioning

confidence: 99%

Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

Wey

Luo

Tseng

et al. 2012

Blood

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Traditionally, GRP78 is regarded as protective against hypoxia and nutrient starvation prevalent in the microenvironment of solid tumors; thus, its role in the development of hematologic malignancies remains to be determined. To directly elucidate the requirement of GRP78 in leukemogenesis, we created a biallelic conditional knockout mouse model of GRP78 and PTEN in the hematopoietic system. Strikingly, heterozygous knockdown of GRP78 in PTEN null mice is sufficient to restore the hematopoietic stem cell population back to the normal percentage and suppress leukemic blast cell expansion. AKT/mTOR activation in PTEN null BM cells is potently inhibited by Grp78 heterozygosity, corresponding with suppression of the PI3K/AKT pathway by GRP78 knockdown in leukemia cell lines. This is the first demonstration that GRP78 is a critical effector of leukemia progression, at least in part through regulation of oncogenic PI3K/AKT signaling. In agreement with PI3K/AKT as an effector for cytosine arabinoside resistance in acute myeloid leukemia, overexpression of GRP78 renders human leukemic cells more resistant to cytosine arabinoside-induced apoptosis, whereas knockdown of GRP78 sensitizes them. These, coupled with the emerging association of elevated GRP78 expression in leukemic blasts of adult patients and early relapse in childhood leukemia, suggest that GRP78 is a novel therapeutic target for leukemia. (Blood. 2012;119(3):817-825) IntroductionOne of the most frequently mutated tumor suppressor genes in human cancer is PTEN (phosphatase and tension homolog deleted on chromosome 10), which encodes for a nonredundant, plasmamembrane lipid phosphatase that antagonizes the phosphatidylinositol-3-kinase (PI3K) signaling pathway. 1,2 On loss of PTEN, the PI3K/AKT signaling pathway is activated, leading to promotion of cell survival, proliferation, and angiogenesis, as well as activation of the mTOR and S6 kinases, resulting in enhanced protein translation commonly observed in cancers. 3 PTEN also has a role in the maintenance of the hematopoietic stem cells (HSCs), as shown by ablation of PTEN function in adult HSCs through crossing of polyinosine-polycytidine (pIpC)-inducible Mx-1-Cre transgenic mouse line 4 with a Pten flox/flox (Pten f/f ) mouse line. 5 Induced Cre expression in postnatal mice exhausted normal HSCs and promoted excessive proliferation of leukemogenic stem cells, resulting in the development of myeloproliferative disorders (MPDs) and eventually leukemia. 6,7 These studies further showed that the mTOR inhibitor rapamycin effectively suppressed growth of the leukemogenic stem cells and prevented exhaustion of normal HSCs. Furthermore, recent studies have shown that PTEN is down-regulated by BCR-ABL in leukemic stem cells, and PI3K and AKT play critical roles in BCR-ABL-induced leukemia in mice. 8,9 Thus, inhibition of the PTEN/AKT/mTOR pathway not only can suppress solid tumor growth but could also represent a novel therapeutic strategy against stem cell disorders that are leukemogenic in nature.GRP78, also ref...

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Section: Knockdown Of Grp78 In Human Leukemic Cells Enhances Arac-indmentioning

confidence: 99%

Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

Wey

Luo

Tseng

et al. 2012

Blood

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“…The authors showed that ATRA induces transient increases in a CNT-type activity that is not yet well characterized but is presumably associated with a polymorphic variant of known CNTs (17). Moreover, ATRA treatment has been shown to increase ara-C transport and ara-C-induced apoptosis (18,19).…”

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confidence: 99%

All-trans-retinoic Acid Promotes Trafficking of Human Concentrative Nucleoside Transporter-3 (hCNT3) to the Plasma Membrane by a TGF-β1-mediated Mechanism

Fernández-Calotti

Pastor‐Anglada

2010

Journal of Biological Chemistry

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Human concentrative nucleoside transporter-3 (hCNT3) is a sodium-coupled nucleoside transporter that exhibits high affinity and broad substrate selectivity, making it the most suitable candidate for mediating the uptake and cytotoxic action of most nucleoside-derived drugs. The drug of this class most commonly used in the treatment of chronic lymphocytic leukemia (CLL) is the pro-apoptotic nucleoside analog fludarabine (Flu), which enters CLL cells primarily through human equilibrative nucleoside transporters (hENTs). Although CLL cells lack hCNT3 activity, they do express this transporter protein, which is located mostly in the cytosol. The aim of our study was to identify agents and mechanisms capable of promoting hCNT3 trafficking to the plasma membrane. Here, we report that all-transretinoic acid (ATRA), currently used in the treatment of acute promyelocytic leukemia (APL), increases hCNT3-related activity through a mechanism that involves trafficking of pre-existing hCNT3 proteins to the plasma membrane. This effect is mediated by the autocrine action of transforming growth factor (TGF)-␤1, which is transcriptionally activated by ATRA in a p38-dependent manner. TGF-␤1 acts through activation of ERK1/2 and the small GTPase RhoA to promote plasma membrane trafficking of the hCNT3 protein.

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“…To get new insights into the mechanisms underlying resistance/susceptibility of AML cells to cytarabine and doxorubicin, human AML cells derived from patients diagnosed with FAB M2 (HL-60 cell line) and FAB M6 - erythroleukemia (KG-1 cell line) were exposed to these chemotherapeutic agents for 18 h, 24 h and 48 h. Two concentrations of cytarabine were used: 10 μM, the most commonly used cytarabine concentration for human AML cell lines in in vitro assays [ 43 - 45 ] and 1000 μM, to mimic chemotherapeutic regimens consisting of high cytarabine concentrations [ 46 , 47 ]. Regarding doxorubicin, the half maximal inhibitory concentrations (IC 50 ) were used (Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Proteolytic systems and AMP-activated protein kinase are critical targets of acute myeloid leukemia therapeutic approaches

et al. 2014

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The therapeutic strategies against acute myeloid leukemia (AML) have hardly been modified over four decades. Although resulting in a favorable outcome in young patients, older individuals, the most affected population, do not respond adequately to therapy. Intriguingly, the mechanisms responsible for AML cells chemoresistance/susceptibility are still elusive. Mounting evidence has shed light on the relevance of proteolytic systems (autophagy and ubiquitin-proteasome system, UPS), as well as the AMPK pathway, in AML biology and treatment, but their exact role is still controversial. Herein, two AML cell lines (HL-60 and KG-1) were exposed to conventional chemotherapeutic agents (cytarabine and/or doxorubicin) to assess the relevance of autophagy and UPS on AML cells’ response to antileukemia drugs. Our results clearly showed that the antileukemia agents target both proteolytic systems and the AMPK pathway. Doxorubicin enhanced UPS activity while drugs’ combination blocked autophagy specifically on HL-60 cells. In contrast, KG-1 cells responded in a more subtle manner to the drugs tested consistent with the higher UPS activity of these cells. In addition, the data demonstrates that autophagy may play a protective role depending on AML subtype. Specific modulators of autophagy and UPS are, therefore, promising targets for combining with standard therapeutic interventions in some AML subtypes.

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All-trans-retinoic acid increases cytosine arabinoside cytotoxicity in HL-60 human leukemia cells in spite of decreased cellular ara-CTP accumulation

Cited by 7 publications

References 26 publications

Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

All-trans-retinoic Acid Promotes Trafficking of Human Concentrative Nucleoside Transporter-3 (hCNT3) to the Plasma Membrane by a TGF-β1-mediated Mechanism

Proteolytic systems and AMP-activated protein kinase are critical targets of acute myeloid leukemia therapeutic approaches

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