Deglycosylated bleomycin induces apoptosis in lymphoma cell via c-jun NH2-terminal kinase but not reactive oxygen species

Brahim, Souhir; Praly, Laurent; Sonia, Yatouji; Delphine, Mérino; Cortier, Marion; Rébé, Cédric; Micheau, Olivier; Kénani, Abderraouf; Bettaieb, Ali

doi:10.1016/j.bcp.2007.07.036

Cited by 9 publications

(2 citation statements)

References 37 publications

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“…Bleomycin is a well characterized agent that induces apoptosis by the JNK-mediated, Bax-dependent mitochondrial pro-death signaling pathway (Lee et al, 2005; Souhir et al, 2007). Both OGD and bleomycin resulted in robust translocation of Bax, PUMA and BimEL to the mitochondria in cortical neurons, and this was significantly attenuated by overexpression of Hsp27 (Figure 5F).…”

Section: Resultsmentioning

confidence: 99%

Hsp27 Protects against Ischemic Brain Injury via Attenuation of a Novel Stress-Response Cascade Upstream of Mitochondrial Cell Death Signaling

Stetler¹,

Cao²,

Gao³

et al. 2008

J. Neurosci.

130

154

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Heat shock protein 27 (Hsp27), a recently discovered member of the heat shock protein family, is markedly induced in the brain after cerebral ischemia and other injury states. In non-neuronal systems, Hsp27 has potent cell death-suppressing functions. However, the mechanism of Hsp27-mediated neuroprotection has not yet been elucidated. Using transgenic and viral overexpression of Hsp27, we investigated the molecular mechanism by which Hsp27 exerts its neuroprotective effect. Overexpression of Hsp27 conferred long-lasting tissue preservation and neurobehavioral recovery, as measured by infarct volume, sensorimotor function, and cognitive tasks up to 3 weeks following focal cerebral ischemia. Examination of signaling pathways critical to neuronal death demonstrated that Hsp27 overexpression led to the suppression of the MKK4/JNK kinase cascade. While Hsp27 overexpression did not suppress activation of an upstream regulatory kinase of the MKK/JNK cascade, ASK1, Hsp27 effectively inhibited ASK1 activity via a physical association through its N-terminal domain and the kinase domain of ASK1. The N-terminal region of Hsp27 was required for neuroprotective function against in vitro ischemia. Moreover, knockdown of ASK1 or inhibition of the ASK1/MKK4 cascade effectively inhibited cell death following neuronal ischemia. This underscores the importance of this kinase cascade in the progression of ischemic neuronal death. Inhibition of PI3K had no effect on Hsp27-mediated neuroprotection, suggesting that Hsp27 does not promote cell survival via activation of PI3K/Akt. Based on these findings, we conclude that overexpression of Hsp27 confers long-lasting neuroprotection against ischemic brain injury via a previously unexplored association and inhibition of ASK1 kinase signaling.

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Section: Resultsmentioning

confidence: 99%

Hsp27 Protects against Ischemic Brain Injury via Attenuation of a Novel Stress-Response Cascade Upstream of Mitochondrial Cell Death Signaling

Stetler¹,

Cao²,

Gao³

et al. 2008

J. Neurosci.

130

154

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“…In another study, no increase in TR/1 and TR/2 receptor levels were reported following bleomycin application compared to the control groups in the lymphoma cell line U937. Inhibition of TRAIL receptors did not interfere with bleomycin-induced apoptosis suggesting presence of a TRAIL receptor-independent mechanism for the apoptotic action of bleomycin [35]. Two other studies by the same researchers revealed that bleomycin-induced apoptosis occurred through caspase pathway, yet was independent of TRAIL receptors [36,37].…”

Section: Discussionmentioning

confidence: 86%

Bleomycin Induced Sensitivity to TRAIL/Apo-2L-Mediated Apoptosis in Human Seminomatous Testicular Cancer Cells is Correlated with Upregulation of Death Receptors

Timur¹,

Çört²,

Ozdemir³

et al. 2014

ACAMC

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The most common solid tumor is testicular cancer among young men. Bleomycin is an antitumor antibiotic used for the therapy of testicular cancer. TRAIL is a proapoptotic cytokine that qualified as an apoptosis inducer in cancer cells. Killing cancer cells selectively via apoptosis induction is an encouraging therapeutic strategy in clinical settings. Combination of TRAIL with chemotherapeutics has been reported to enhance TRAIL-mediated apoptosis of different kinds of cancer cell lines. The molecular ground for sensitization of tumour cells to TRAIL by chemotherapeutics might involve upregulation of TRAIL-R1 (TR/1, DR4) and/or TRAIL-R2 (TR/2, DR5) receptors or activation of proapoptotic proteins including caspases. The curative potential of TRAIL to eradicate cancer cells selectively in testicular cancer has not been studied before. In this study, we investigated apoptotic effects of bleomycin, TRAIL, and their combined application in NTera-2 and NCCIT testicular cancer cell lines. We measured caspase 3 levels as an apoptosis indicator, and TRAIL receptor expressions using flow cytometry. Both NTera-2 and NCCIT cells were fairly resistant to TRAIL's apoptotic effect. Incubation of bleomycin alone caused a significant increase in caspase 3 activity in NCCIT. Combined incubation with bleomycin and TRAIL lead to elevated caspase 3 activity in Ntera-2. Exposure to 72 h of bleomycin increased TR/1, TR/2, and TR/3 cell-surface expressions in NTera-2. Elevation in TR/1 cell-surface expression was evident only at 24 h of bleomycin application in NCCIT. It can be concluded that TRAIL death receptor expressions in particular are increased in testicular cancer cells via bleomycin treatment, and TRAIL-induced apoptosis is initiated.

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The combination of Bleomycin with TRAIL agonists or PKC inhibitors sensitizes solid tumor cells to BLM-mediated apoptosis: new strategies to overcome chemotherapy resistance of tumors

Brahim¹,

Aroui²,

Ali³

et al. 2017

Med Chem Res

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IF 1.436International audienceIn this study we evaluated the effects of low dose of bleomycin in an associative treatment strategy in solid tumor cells. For this purpose, Human and murine colon cancer (SW480, HCT8, and CT26), and murine melanoma (B16-F10) cells were treated with different agents including protein kinase C, and c-jun NH2-terminal kinase inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand. Apoptosis was identified by morphological criteria. Reactive oxygen species are evaluated by flow cytometry. Our data showed that bleomycin (100 µM) induced apoptosis in all the four cell lines tested with a level ranging from 30 to 60%. However, at lower dose (25 µM), bleomycin was less efficient to trigger apoptosis. In contrast, when bleomycin (25 µM) was combined with the protein kinase C inhibitor chelerythrine, or tumor necrosis factor-related apoptosis-inducing ligand, it elicited more apoptotic cell death ranging from 40 to 75%, depending on the cell type, whereas when it was associated with the c-jun NH2-terminal kinase inhibitor SP600125, bleomycin displayed different cell death responses. If bleomycin and SP600125 enhanced apoptosis in two colon cancer cells, HCT-8, and CT26, they reduced to 50% apoptosis in the melanoma B16-F10 cells, and were not synergistic in the human colon cancer cells, SW480. This synergism seemed to rely partially to reactive oxygen species, because N-acetyl cysteine inhibited apoptosis in some cells and with some agents. These findings indicate that tumor necrosis factor-related apoptosis-inducing ligand, and protein kinase C inhibition can represent candidates for improved cancer chemotherapy

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Deglycosylated bleomycin induces apoptosis in lymphoma cell via c-jun NH2-terminal kinase but not reactive oxygen species

Cited by 9 publications

References 37 publications

Hsp27 Protects against Ischemic Brain Injury via Attenuation of a Novel Stress-Response Cascade Upstream of Mitochondrial Cell Death Signaling

Hsp27 Protects against Ischemic Brain Injury via Attenuation of a Novel Stress-Response Cascade Upstream of Mitochondrial Cell Death Signaling

Bleomycin Induced Sensitivity to TRAIL/Apo-2L-Mediated Apoptosis in Human Seminomatous Testicular Cancer Cells is Correlated with Upregulation of Death Receptors

The combination of Bleomycin with TRAIL agonists or PKC inhibitors sensitizes solid tumor cells to BLM-mediated apoptosis: new strategies to overcome chemotherapy resistance of tumors

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