The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells

Abstract Thymidylate synthase (TS) inhibition causes cell death, and this enzyme is the target for the important chemotherapy regime 5-fluorouracil/leucovorin. GW1843 (1843U89) is a potent and specific folate analog TS inhibitor in clinical development. Because of the importance of TS as a chemotherapy target, we are studying the mechanism of TS inhibition-induced cell death by GW1843. Ceramide is a regulatory lipid generated by the action of sphingomyelinase and is believed to signal apoptosis. The role of the ceramide in apoptotic signaling was studied in Molt-4 human T-cell leukemia cells undergoing cell death after treatment with GW1843. In response to GW1843, Molt-4 cells undergo apoptosis with both acidic pH, Mg2+-independent sphingomyelinase (ASMase) and neutral pH, Mg2+-dependent sphingomyelinase (NSMase) activities elevated as early steps in the initiation of apoptosis before Molt-4 commitment to death. These activities lead to ceramide production with kinetics consistent with a role as an effector molecule signaling the initiation of apoptosis in Molt-4 cells. These changes were found to be independent of caspase 3–like (CPP32/apopain) activity and DNA degradation, but were not separable from membrane blebbing or cell lysis in this cell line. In this report, kinetic evidence is provided for a role of ceramide in initiating GW1843-induced cell death of Molt-4 T-cell leukemia cells.

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Role of microRNA-143 in Fas-mediated apoptosis in human T-cell leukemia Jurkat cells

Leukemia Research ◽

10.1016/j.leukres.2009.04.019 ◽

2009 ◽

Vol 33 (11) ◽

pp. 1530-1538 ◽

Cited By ~ 60

Author(s):

Yukihiro Akao ◽

Yoshihito Nakagawa ◽

Akio Iio ◽

Tomoki Naoe

Keyword(s):

T Cell ◽

Jurkat Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Human T Cell

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Emodin and DHA potently increase arsenic trioxide interferon-α–induced cell death of HTLV-I–transformed cells by generation of reactive oxygen species and inhibition of Akt and AP-1

Blood ◽

10.1182/blood-2006-04-015537 ◽

2006 ◽

Vol 109 (4) ◽

pp. 1653-1659 ◽

Cited By ~ 64

Author(s):

Megan Brown ◽

Marcia Bellon ◽

Christophe Nicot

Keyword(s):

Cell Death ◽

T Cell ◽

Arsenic Trioxide ◽

Interferon Α ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Clinical Prognosis ◽

Human T Cell

Abstract Adult T-cell leukemia (ATL) is an aggressive lymphoproliferative disease of poor clinical prognosis associated with infection by the human T-cell leukemia virus type I (HTLV-I). The use of arsenic trioxide (As2O3) has been shown to effectively treat acute promyelocytic leukemia (APL) with greater than 80% of patients achieving complete remission. The combination of arsenic and interferon has also shown promising results in the treatment of ATL. The requirement for slow dosage increases of arsenic and the time required to achieve a pharmacologic active dose in patients is a major obstacle because median survival of patients with ATL is about 6 months. In this study we report a potent synergistic effect of the combination of arsenic trioxide and interferon α (As/IFN-α) with emodin and DHA on cell-cycle arrest and cell death of HTLV-I–infected cells. Importantly, we found that clinically achievable doses of DHA and emodin allowed for reduced arsenic concentrations by 100-fold while still remaining highly toxic to tumor cells. Our data provide a rationale for combined use of As/IFN-α with emodin and DHA in patients with ATL refractory to conventional therapy.

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Acacetin induces apoptosis in human T cell leukemia Jurkat cells via activation of a caspase cascade

Oncology Reports ◽

10.3892/or.2011.1498 ◽

2011 ◽

Cited By ~ 2

Author(s):

Shin Yomogida

Keyword(s):

T Cell ◽

Jurkat Cells ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Human T Cell ◽

Caspase Cascade

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Restoration of ceramide de novo synthesis by the synthetic retinoid ST1926 as it induces adult T-cell leukemia cell death

Bioscience Reports ◽

10.1042/bsr20200050 ◽

2020 ◽

Vol 40 (10) ◽

Author(s):

Botheina Ghandour ◽

Claudio Pisano ◽

Nadine Darwiche ◽

Ghassan Dbaibo

Keyword(s):

Cell Death ◽

T Cell ◽

De Novo ◽

Leukemia Cell ◽

T Cell Leukemia ◽

Ceramide Synthase ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Synthetic Retinoid ◽

Human T Cell

Abstract Ceramide (Cer) is a bioactive cellular lipid with compartmentalized and tightly regulated levels. Distinct metabolic pathways lead to the generation of Cer species with distinguishable roles in oncogenesis. Deregulation of Cer pathways has emerged as an important mechanism for acquired chemotherapeutic resistance. Adult T-cell leukemia (ATL) cells are defective in Cer synthesis. ATL is an aggressive neoplasm that develops following infection with human T-cell lymphotropic virus-1 (HTLV-1) where the viral oncogene Tax contributes to the pathogenesis of the disease. ATL cells, resistant to all-trans-retinoic acid, are sensitive to pharmacologically achievable concentrations of the synthetic retinoid ST1926. We studied the effects of ST1926 on Cer pathways in ATL cells. ST1926 treatment resulted in early Tax oncoprotein degradation in HTLV-1-treated cells. ST1926 induced cell death and a dose- and time-dependent accumulation of Cer in malignant T cells. The kinetics and degree of Cer production showed an early response upon ST1926 treatment. ST1926 enhanced de novo Cer synthesis via activation of ceramide synthase CerS(s) without inhibiting dihydroceramide desaturase, thereby accumulating Cer rather than the less bioactive dihydroceramide. Using labeling experiments with the unnatural 17-carbon sphinganine and measuring the generated Cer species, we showed that ST1926 preferentially induces the activities of a distinct set of CerS(s). We detected a delay in cell death response and interruption of Cer generation in response to ST1926 in Molt-4 cells overexpressing Bcl-2. These results highlight the potential role of ST1926 in inducing Cer levels, thus lowering the threshold for cell death in ATL cells.

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T-cell activation signals and human T-cell leukemia virus type I-encoded p40x protein activate the mouse granulocyte-macrophage colony-stimulating factor gene through a common DNA element

Molecular and Cellular Biology ◽

10.1128/mcb.8.12.5581-5587.1988 ◽

1988 ◽

Vol 8 (12) ◽

pp. 5581-5587

Author(s):

S Miyatake ◽

M Seiki ◽

M Yoshida ◽

K Arai

Keyword(s):

T Cell ◽

Simian Virus 40 ◽

Simian Virus ◽

Jurkat Cells ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Gm Csf ◽

Human T Cell

Activation of T cells by an antigen, a mitogen, or a combination of a phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA]) and a calcium ionophore (A23187) leads to induction of a set of lymphokine genes. Treatment of human T-cell leukemia line Jurkat by a mitogen or p40x, a transactivator protein encoded by human T-cell leukemia virus type I, activates many transfected lymphokine genes in a transient transfection assay. To study the mechanism of lymphokine gene induction, we examined the effects of mitogen stimulation and p40x on the gene for the mouse granulocyte-macrophage colony-stimulating factor (GM-CSF) in Jurkat cells. Deletion and mutation analyses showed that the 5'-flanking region of the gene for the GM-CSF is composed of two types of regulatory elements. One sequence, located at positions -95 to -73, determines response to stimulation by either TPA-A23187 or p40x. This region contains conserved lymphokine element 2, which appears in the gene for interleukin 3 (IL-3) and is followed by a GC-rich stretch. This GC-rich stretch alone specifies inducible response to p40x but not to TPA-A23187. Another sequence, located at positions -113 to -96 upstream of a TATA-like sequence, mediates inducible response to p40x but not to TPA-A23187. This sequence includes conserved lymphokine element 1, which appears in several lymphokine-cytokine genes, such as those for IL-3, G-CSF, and IL-2. We previously showed that the simian virus 40 early region promoter was also induced by a mitogen or p40x in Jurkat cells. Deletion analysis showed that the minimum region require for stimulation by both signals are identical. These results, which indicate that p40(x) stimulates transcription of the gene for the GM-CSF or the simian virus 40 early region promoter through the same DNA element or an overlapping DNA element required for induction by a mitogen, lend further support to the notion that p40(x) can exert its function by activating a component(s) of the T-cell signal transduction pathway which is activated by an antigen or a mitogen.

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