Phosphatase and tensin analog gene overexpression engenders cellular death in human malignant mesothelioma cells via inhibition of AKT phosphorylation

Mohiuddin, Imran; Cao, Xuanye; Özvaran, Mustafa Kürşat; Zumstein, Lou; Chada, Sunil; Smythe, W. Roy

doi:10.1007/bf02573071

Cited by 21 publications

(9 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regulation of Bcl2 by PTEN was on the transcriptional level and exogenous expression of Bcl2 was able to attenuate PTEN-induced chemosensitivity in LNCaP cells (Huang et al, 2001). Similar results have been observed in thyroid cancer cells, breast carcinoma cells and malignant mesothelioma cells (Ghosh et al, 1999;Weng et al, 2001a, c;Mohiuddin et al, 2002).…”

Section: Pten Signaling As a Lipid Phosphatasementioning

confidence: 53%

PTEN signaling pathways in melanoma

2003

View full text Add to dashboard Cite

Section: Pten Signaling As a Lipid Phosphatasementioning

confidence: 53%

PTEN signaling pathways in melanoma

2003

View full text Add to dashboard Cite

“…PI3K/Akt signalling pathway is negatively regulated by the tumour suppressor gene phosphatase and tensin homologue (PTEN). Over-expression of PTEN engenders apoptosis in MM by AKT hypophosphorylation [33]. In light of these facts it is possible to suppose that over-expression of PTEN could be the basis of hypophosphorylated Akt in the Ist-Mes-2 cell line.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of gefitinib and rofecoxib in mesothelioma cells

Stoppoloni¹,

Canino²,

Cardillo³

et al. 2010

Mol Cancer

View full text Add to dashboard Cite

BackgroundMalignant mesothelioma (MM) is an aggressive tumor that is resistant to conventional modes of treatment with chemotherapy, surgery or radiation. Research into the molecular pathways involved in the development of MM should yield information that will guide therapeutic decisions. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are involved in the carcinogenesis of MM. Combination of COX-2 and EGFR inhibitors, therefore, could be an effective strategy for reducing cell growth in those lines expressing the two molecular markers.ResultsIn order to verify the effect of COX-2 and EGFR inhibitors, five MM cell lines NCI-2452, MPP89, Ist-Mes-1, Ist-Mes-2 and MSTO-211 were characterized for COX-2 and EGFR and then treated with respective inhibitors (rofecoxib and gefitinib) alone and in combination. Only MPP89, Ist-Mes-1 and Ist-Mes-2 were sensitive to rofecoxib and showed growth-inhibition upon gefitinib treatment. The combination of two drugs demonstrated synergistic effects on cell killing only in Ist-Mes-2, the cell line that was more sensitive to gefitinib and rofecoxib alone. Down-regulation of COX-2, EGFR, p-EGFR and up-regulation of p21 and p27 were found in Ist-Mes-2, after treatment with single agents and in combination. In contrast, association of two drugs resulted in antagonistic effect in Ist-Mes-1 and MPP89. In these cell lines after rofecoxib exposition, only an evident reduction of p-AKT was observed. No change in p-AKT in Ist-Mes-1 and MPP89 was observed after treatment with gefitinib alone and in combination with rofecoxib.ConclusionsGefitinib and rofecoxib exert cell type-specific effects that vary between different MM cells. Total EGFR expression and downstream signalling does not correlate with gefitinib sensitivity. These data suggest that the effect of gefitinib can be potentiated by rofecoxib in MM cell lines where AKT is not activated.

show abstract

“…Amplification and mutation of PI3K and AKT genes have also been reported in several tumor types [88]. Although at present mutation or amplification of PI3K and AKT do not appear to occur and loss of PTEN seems to be infrequent in MM [60,89,90], the PI3K/AKT pathway has been reported to be aberrantly activated in this tumor. In particular, an elevated activity of AKT has been observed in more than two-thirds of MM tissues [60,91].…”

Section: Inhibition Of Intracellular Signaling Effectors: Targeting Tmentioning

confidence: 94%

“…In addition, high levels of activated AKT have been found in MM cell lines in association with a SV40-positive status and/or with activated signaling from several growth factor receptors, including those for HGF, VEGF, PDGF and EGF [20,57,66,92,93]. Furthermore, it has been demonstrated that AKT plays an important role in asbestos-induced mesothelial cell transformation and that inhibition of the PI3K/AKT pathway can induce growth arrest and apoptosis, reduce migration and invasion and sensitize MM cells to different anticancer agents [8,[90][91][92][93][94][95][96][97]. Collectively, these findings provide a strong rationale for targeting the PI3K/AKT signaling axis in MM patients.…”

Section: Inhibition Of Intracellular Signaling Effectors: Targeting Tmentioning

confidence: 96%

Molecular Targets and Targeted Therapies for Malignant Mesothelioma

Palumbo

Bei

Procopio

et al. 2008

CMC

View full text Add to dashboard Cite

Malignant mesothelioma is a highly invasive tumor originating from the mesothelial linings of the pleura, peritoneum and pericardium. It is seldom amenable to surgical intervention and poorly responsive to radiotherapy, leaving chemotherapy as the main therapeutic option for most patients. The development of effective drug regimens against mesothelioma has proven extremely difficult and a standard first-line treatment for patients with unresectable tumors has not been established until recently. Despite the benefits obtained with this newly validated standard of care, which is based on the combination of pemetrexed and cisplatin, the prognosis for mesothelioma patients remains poor, median survival is still less than two years and more active treatments are urgently needed. This article will focus on the molecular basis providing the rationale for targeted interventions against mesothelioma and will review targeted agents under evaluation as new potential therapeutic options for mesothelioma patients. Such agents include inhibitors of growth factor receptors, ligands and intracellular effectors. The agents targeting vascular endothelial growth factor signaling are of particular interest, due to the involvement of this pathway both in tumor angiogenesis and autocrine stimulation of mesothelioma cell growth. Alternative approaches are based on inhibitors of the ubiquitin-proteasome pathway and of histone deacetylases which, notwithstanding the functional divergence of the corresponding targets, share the ability to determine a wide modulation of the cancer cell phenotype that can lead to cell cycle arrest, apoptosis and sensitization to different antineoplastic treatments. A recombinant immunotoxin targeted to the membrane antigen mesothelin is an additional agent whose activity is being evaluated in mesothelioma patients.

show abstract

Phosphatase and tensin analog gene overexpression engenders cellular death in human malignant mesothelioma cells via inhibition of AKT phosphorylation

Abstract: Overexpression of PTEN engenders apoptosis in mesothelioma by AKT hypophosphorylation. The forced overexpression of PTEN may prove useful clinically in this treatment-resistant neoplasm.

Cited by 21 publications

References 24 publications

PTEN signaling pathways in melanoma

PTEN signaling pathways in melanoma

Synergistic effect of gefitinib and rofecoxib in mesothelioma cells

Molecular Targets and Targeted Therapies for Malignant Mesothelioma

Contact Info

Product

Resources

About