Reactive Oxygen Species Generation and Mitochondrial Dysfunction in the Apoptotic Response to Bortezomib, a Novel Proteasome Inhibitor, in Human H460 Non-small Cell Lung Cancer Cells

Ling, Yi He; Liebes, Leonard; Zou, Yiyu; Pérez-Soler, Román

doi:10.1074/jbc.m302559200

Cited by 432 publications

(332 citation statements)

References 47 publications

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“…We as well as other groups have recently confirmed the involvement of the mitochondrial pathway and of caspases in apoptosis due to proteasome inhibition [13][14][15][16][17]. The observation of cytochrome c cytosolic relocalization and DW m dissipation in DC treated with bortezomib demonstrates the eventual loss of mitochondria integrity in response to this drug.…”

Section: Discussionsupporting

confidence: 67%

“…The mitochondrial apoptotic pathway has been shown to play a role in proteasome inhibitor-induced apoptosis in several tumor cell models [13][14][15][16][17][18][19]. Therefore, we evaluated mitochondria integrity in DC exposed to bortezomib.…”

Section: Mitochondrial Damage In Response To Bortezomib In DCmentioning

confidence: 99%

“…How proteasome inhibition translates into a potent cytotoxic effect in tumor cells is not fully understood, even though inhibition of NF-jB and deregulated expression of p53, caspases, Bcl-2 family members, CDC25 family proteins and cyclins were all proposed to be relevant in this context [1,2]. Ultimately, deregulated protein turnover by proteasome inhibition leads to activation of the intrinsic apoptotic pathway as shown by mitochondria dysfunction, production of reactive oxygen species, and endoplasmic reticulum stress, which have all been observed in response to these drugs [13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

et al. 2006

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Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen‐presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte‐derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up‐regulation and intracellular redistribution of Bcl‐2‐associated X protein (Bax), a pro‐apoptotic Bcl‐2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen‐presenting cell level.

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Section: Discussionsupporting

confidence: 67%

Section: Mitochondrial Damage In Response To Bortezomib In DCmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

et al. 2006

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“…Bortezomib was reported to induce ROS generation in various cancer cells such as non-small-cell lung cancer, leukaemia cells, and head and neck squamous cell carcinoma. ROS was therefore implicated as the primary cause for bortezomib-induced apoptosis of those cells (Ling et al, 2003;Fribley et al, 2004;Yu et al, 2004;Landowski et al, 2005). Recent reports have demonstrated that NF-kB indirectly inhibits ROS generation (Sakon et al, 2003;Kamata et al, 2005); however, the intracellular ROS balance may be regulated by multiple pathways, therefore, it is still uncertain whether ROS generation is due to NF-kB/I-kB inhibition cascade in bortezomib-treated cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells

et al. 2007

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Adult T-cell leukaemia (ATL) is a lethal neoplasia derived from HTLV-1-infected T lymphocytes frequently exhibiting nuclear factorkB (NF-kB) activation. Despite the use of various treatment regimens, the prognosis of ATL is poor, and new treatment strategies are urgently needed. We therefore explored the effect and the molecular mechanism of a proteasome inhibitor, bortezomib, in ATL cells. We found bortezomib-induced cell death, and bortezomib suppressed constitutive NF-kB activation via I-kB stabilisation in three ATL cell lines (TaY, MT-2 and MT-4). An oligonucleotide DNA microarray analysis of TaY cells revealed upregulation of genes encoding heat shock proteins (HSPA1A, STIP1, HSPA1B, and HSPCA), genes related to protein folding (CDC37 and ANAPC5), Fasassociated factor 1(FAF1) and an oxidative stress-related gene, heme oxygenase-1(HMOX-1), known to be a target gene of hypoxiainducible gene-1 alpha (HIF-1 alpha). Cobalt protoporphyrin induced HMOX-1, instead of HIF-1 alpha expression and increased bortezomib-induced apoptosis in the presence of pharmacologically effective doses of bortezomib. In contrast, zinc protoporphyrin downregulated HMOX-1 expression, thereby partially inhibiting bortezomib-induced cell death. This indicates that HMOX-1 may modulate anticancer effects of bortezomib in ATL cells, and could be a molecular target in treating ATL patients.

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“…Previous experimental evidences suggested a correlation between the mutational status in B-RAF and the melanoma susceptibility to chemotherapeutic drugs, 5 such as paclitaxel and doxorubicin [6][7][8][9][10][11][12][13][14][15][16][17][18] , which are able to generate an accumulation of hydrogen peroxide (H 2 O 2 ) in the cells. In particular, melanoma cell lines wild-type in B-RAF (SK23Mel, WM266Mel) have been reported more resistant to paclitaxel and doxorubicin 5 compared to the ones mutated in B-RAF (A375, SKMel 13, SKMel19, M14).…”

Section: Introductionmentioning

confidence: 99%

c-Myc modulation: a key role in melanoma drug response

Fico

Alfano

Valentino

et al. 2015

Cancer Biology & Therapy

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Reactive Oxygen Species Generation and Mitochondrial Dysfunction in the Apoptotic Response to Bortezomib, a Novel Proteasome Inhibitor, in Human H460 Non-small Cell Lung Cancer Cells

Cited by 432 publications

References 47 publications

Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells

c-Myc modulation: a key role in melanoma drug response

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