Absence of p53 mutations in malignant mesotheliomas.

Mor, Orna; Yaron, Pnina; Huszar, Monica; Yellin, Allon; Jakobovitz, Orit; Brok‐Simoni, Frida; Rechavi, Gideon; Reichert, Nira

doi:10.1165/ajrcmb.16.1.8998073

Cited by 81 publications

(41 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Additionally, nuclear positivity for pSTAT3 has been described in 60% of malignant mesothelioma cases (Achcar Rde et al, 2007). Our data suggest that the involvement of p53 pathway in MPM, typically considered as a wtp53-carrying tumor (Metcalf et al, 1992;Mor et al, 1997), must be further investigated. We show that RNAi-mediated (Figure 6).…”

Section: Discussionmentioning

confidence: 77%

SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells

Canino¹,

Mori²,

et al. 2011

View full text Add to dashboard Cite

Here we show that pemetrexed-treated mesothelioma cells undergo accelerated senescence. This is characterized by the secretion of proinflammatory and mitogenic cytokines, reminiscent of an SASP (senescence-associated secretory phenotype). Conditioned media from senescent MPM (malignant pleural mesothelioma) cells trigger the emergence of EMT (epithelial-to-mesenchymal)-like, clonogenic and chemoresistant cell subpopulations, expressing high levels of ALDH (aldehyde dehydrogenase) activity (ALDH bright cells). We show by fluorescence-activated cell sorting of purified ALDH bright and ALDH low cells, that both cell-autonomous and cell-non-autonomous mechanisms converge to maintain the SASP-induced, EMT-like cell subpopulations. Chemoresistant ALDH bright cells exist within primary MPM specimens and enrichment for ALDH bright cells correlates with an earlier tumor onset into NOD/SCID mice. We show that RAS v12 expression induces SASP-like changes in untransformed human mesothelial cells, and that p53 ablation increases the effect of RAS v12 expression. We identify STAT3 activation as a crucial event downstream to SASP signaling. In fact, small hairpin RNA-mediated ablation of STAT3 deeply attenuates the induction of EMT genes and the increase of ALDH bright cells induced by SASP-cytokines. This strongly affects the chemoresistance of MPM cells in vitro and leads to anticancer effects in vivo.

show abstract

Section: Discussionmentioning

confidence: 77%

SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells

Canino¹,

Mori²,

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Mesothelioma most likely has abnormal function of the p53 pathway, e.g. because of mutation or loss of p14ARF (38) or to interaction with simian virus 40 large T antigen (39), even though the tumor often expresses wild-type p53 (20). Thus, as for most tumors, therapeutic approaches successful in p53 inactive cells would be desirable.…”

Section: Discussionmentioning

confidence: 99%

“…chemotherapy or ␥ irradiation) that were not due to up-regulation of TRAIL receptors, DR4 and DR5 (19). In part because mesothelioma is reported to express wild-type p53 (20), we investigated whether p53 was involved in either synergy or in a p53-dependent JNK activation. We found that these cells had nonfunctional p53.…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…3,4 In this malignancy, which is extremely rich in peculiarities, p53 mutations are uncommon. [3][4][5] This certainty may suggest that alterations in the expression of this gene are unlikely to be responsible for either the creation of an MPM phenotype or MPM insensitivity to apoptotic induction itself. In simian virus 40 (SV40)-positive MPM, this occurrence may be explained by an inactivation of the p53 function coming from the viral TAG.…”

Section: T Rmentioning

confidence: 99%

Retracted: Tumor necrosis factor enhances SN38‐mediated apoptosis in mesothelioma cells

Russo

Catassi

Malacarne

et al. 2005

Cancer

View full text Add to dashboard Cite

In the April 1, 2005, issue of Cancer, an article entitled “Tumor necrosis factor enhances SN38‐mediated apoptosis in mesothelioma cells: The role of nuclear factor‐κB pathway activation” was published by Dr. Russo and colleagues. On October 6, 2009, we were alerted to concerns about the integrity of the data in the article. A formal investigation was conducted by the Institutional Office for Research Integrity (UIR) at the National Institute for Cancer Research (IST) in Genoa, Italy. The investigation report from the UIR President, dated November 4, 2009, stated the following:“1) The internal investigation is concluded and no further analyses are planned on the issue.2) The UIR concluded that the article contains evidence of data fabrication/duplication.3) All the authors (either belonging or not to the IST) have been informed of the concerns about data integrity. Some authors acknowledged the conclusion stated in the previous point 2, others did not; however, none of them accepted the responsibility of having fabricated the data.”Based on this report and our concerns about the validity of the study, we hereby retract this article from Cancer and from the medical literature.Raphael E. Pollock, MD, PhD

show abstract

Absence of p53 mutations in malignant mesotheliomas.

Cited by 81 publications

References 24 publications

SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells

SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma 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

Retracted: Tumor necrosis factor enhances SN38‐mediated apoptosis in mesothelioma cells

Contact Info

Product

Resources

About