Resistance of pleural mesothelioma cell lines to apoptosis: relation to expression of Bcl-2 and Bax

Narasimhan, Sudha Rani; Yang, Lin; Gerwin, Brenda I.; Broaddus, V. Courtney

doi:10.1152/ajplung.1998.275.1.l165

Cited by 65 publications

(85 citation statements)

References 36 publications

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“…We and others have previously demonstrated that MM cell lines show low susceptibility to TRAIL (Liu et al, 2001;Tomasetti et al, 2004) (Vivo et al, 2003) and that this is not due to Bcl-2 (Narasimhan et al, 1998). Here, we show that, although MM primary cells and cell lines express Fas and DR4/DR5, they are not killed by their crosslinking.…”

Section: Introductionsupporting

confidence: 59%

FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

Rippo¹,

Moretti²,

Vescovi³

et al. 2004

Oncogene

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Tumors have developed several forms of resistance to receptor-induced cell death. Here, we show that malignant mesothelial (MM) cell lines as well as primary MM cells and normal mesothelial (NM) cells express Fas and TNFrelated apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. We found that, although Fas expression levels are comparable, only MM cells are resistant to cell death. Furthermore, MM cells show resistance to TRAILinduced apoptosis. Caspase-8 (FLICE) is not activated by death receptors triggering in malignant cells whereas it is well activated by nonreceptor stimuli, such as UV radiation. We found that FLIP (FLICE-Inhibitory Protein) is constitutively expressed in all MM cell lines and is more expressed in primary MM cells than in NM cells. Knockdown of FLIP expression in MM cell lines, by a FLIPsiRNA, re-established the normal response to apoptosis induced by Fas or DR4/DR5, which was blocked by pretreatment with the caspase-8 inhibitor z-IETD-fmk. These results indicate that MM cells develop an intrinsic resistance to apoptosis induced by death receptors upregulating the expression of the antiapoptotic protein c-FLIP.

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Section: Introductionsupporting

confidence: 59%

FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

Rippo¹,

Moretti²,

Vescovi³

et al. 2004

Oncogene

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“…Because mesothelioma is a tumor highly resistant to therapy, strategies that would enhance its response to chemotherapy could provide a useful therapeutic adjunct (37). Mesothelioma most likely has abnormal function of the p53 pathway, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…In primary fibroblasts with targeted gene disruption of JNK1 and JNK2, JNK-induced apoptosis has been shown to depend on its actions at the mitochondria (36) and to require the presence of the pro-apoptotic members of the Bcl-2 family, Bax and Bak (53). We have previously shown that mesothelial cell lines, including M28 and REN, highly express Bax and postulated that this would allow the cells to respond to appropriate apoptotic signals directed to the mitochondria (37). In that case, perhaps, enhanced JNK signals caused by TRAIL plus etoposide would be sufficient to sensitize the mitochondria to respond to TRAILinduced BID signals, mediating synergy.…”

Section: Discussionmentioning

confidence: 99%

c-Jun N-terminal Kinase Contributes to Apoptotic Synergy Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand plus DNA Damage in Chemoresistant, p53 Inactive Mesothelioma Cells

Vivo

Liu

Broaddus

2003

Journal of Biological Chemistry

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Apoptotic resistance of cancer cells may be overcome by the combination of treatments that activate the two major apoptotic pathways: (i) the death receptor pathway activated by death ligands and (ii) the DNA damage pathway activated by chemotherapy. We have previously shown that mesothelioma cells, resistant to most treatments, are sensitive to the combination of the death ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL/Apo2L) plus chemotherapy. We investigated a possible role for c-Jun N-terminal kinase (JNK) in the synergistic effect, knowing that JNK can be activated separately by TRAIL and by DNA damage. We chose to study the M28 and REN human mesothelioma cell lines, which are p53-inactivated, to avoid an interaction between p53 and JNK. We showed that JNK was activated by TRAIL and by etoposide and that the activation was enhanced by the combination of the two treatments. We found this activation to be caspase-independent. To inhibit the JNK pathway, we used either dominant-negative constructs of JNK1 and JNK2 (compared with dominant-negative caspase 9) or a chemical inhibitor of the JNK pathway (SP600125). In cells treated with TRAIL plus etoposide, JNK inhibition increased cell survival and decreased apoptosis significantly. In transfected M28 cells, the effect of JNK inhibition was as great as that of the dominant-negative caspase 9 construct. We conclude that JNK contributes to the synergistic effect of TRAIL combined with DNA damage by mediating signals independent of p53 leading to apoptosis.

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“…Indeed, resistance to apoptosis could explain MM's striking insensitivity to traditional therapy. Asbestos fibers cause apoptosis of normal mesothelial cells; however, mesothelioma cell lines are resistant to apoptosis due to exposure to asbestos fibers, H 2 O 2 , and calcium ionophore (5). This resistance to apoptosis is not affected by the presence of p53, and Bcl-2 is not overexpressed in mesothelioma cells.…”

Section: Introductionmentioning

confidence: 97%

The Effects of Taurolidine, a Novel Antineoplastic Agent, on Human Malignant Mesothelioma

Nici

Monfils

Calabresi

2004

Clinical Cancer Research

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Results: A 72-h exposure of MM cells to taurolidine showed IC 50 of 28 -42.7 M and 50% viability at 49.8 -135 M. Annexin V assay for apoptosis revealed significant increases in annexin binding after 24 -72-h exposure to 50 -150 M taurolidine (P < 0.05), which was significantly inhibited by z-VAD (P < 0.05). MM cells exposed to 50 -150 M taurolidine for 24 -72 h showed terminal deoxynucleotidyl transferase-mediated nick end labeling staining consistent with apoptosis, as well as structural evidence of apoptosis via electron microscopy. In vivo, there were significant tumor reductions (62 to >99% reduction) for all dosage regimens compared with untreated controls (P < 0.001). In addition, all control animals exhibited ascites and diaphragmatic tumors while treated animals did not.Conclusions: Taurolidine has significant antineoplastic activity against MM in vitro and in vivo, in part, due to tumor cell apoptosis. These findings warrant further study for potential clinical usefulness.

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Resistance of pleural mesothelioma cell lines to apoptosis: relation to expression of Bcl-2 and Bax

Cited by 65 publications

References 36 publications

FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

c-Jun N-terminal Kinase Contributes to Apoptotic Synergy Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand plus DNA Damage in Chemoresistant, p53 Inactive Mesothelioma Cells

The Effects of Taurolidine, a Novel Antineoplastic Agent, on Human Malignant Mesothelioma

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