Mutational analysis of the PTEN/MMAC1 tumour suppressor gene in primary human malignant mesotheliomas

Papp, Thilo; Schipper, Holger; Pemsel, Heidi; Unverricht, Marcus; Müller, Klaus‐Michael; Wiethege, Thorsten; Schiffmann, Dietmar; Rahman, Qamar

doi:10.3892/or.8.6.1375

Cited by 10 publications

(9 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus the frequency of AKT activation in MMs in our study using cell lines seems to be very similar to that of previous studies. Whereas one previous study reported that no PTEN mutation was detected in 18 MM specimens, another study demonstrated that a homozygous deletion of PTEN was detected in 1 of 9 MM cell lines (25,26). Thus, our finding that a PTEN homozygous deletion, but not point mutation, was present in 2 (9.5%) of 21 MM cell lines is compatible with the results of previous studies.…”

Section: Discussionsupporting

confidence: 83%

“…There, AKT is phosphorylated and activated by phosphoinositide-dependent kinase 1 (PDK1). In tumor cells, AKT can be activated by a variety of mechanisms, including the loss of PTEN, mutation of the PI3K catalytic subunit gene PIK3CA, and activation of PI3K via autocrine or paracrine (26). To the best of our knowledge, there have been no detailed reports analyzing PIK3CA and LKB1 mutation status in MM.…”

Section: Introductionmentioning

confidence: 90%

See 1 more Smart Citation

Activation of the PI3K-AKT pathway in human malignant mesothelioma cells

Suzuki

Murakami²,

Kawaguchi³

et al. 2009

Mol Med Rep

View full text Add to dashboard Cite

Abstract. Malignant mesothelioma (MM) is a highly aggressive neoplasm, which is associated with asbestos exposure. The dysregulated phosphatidylinositol 3-kinase (PI3K)-AKT pathway plays an important role in cell proliferation, survival and motility in various cancers. In this study, we analyzed the activation status and underlying mechanisms of this pathway in MM cells using 21 cell lines. AKT activation was observed in 13 (62%) of the 21 MM cell lines under serum-starved conditions. Two cell lines, ACC-MESO-1 and Y-MESO-25, showed no expression of PTEN protein, while 7 other cell lines showed low expression of PTEN mRNA and protein compared to expression levels in an immortalized normal mesothelial cell line, MeT-5A. We found that PTEN inactivation in the ACC-MESO-1 and Y-MESO-25 lines was due to a 39.4-kb deletion including PTEN exon 2, and to a 7.7-kb deletion including exon 1, respectively. Re-expression of PTEN in these cells reduced the activity of colony formation in vitro. In contrast, no mutation of PIK3CA or LKB1 was found in any of the MM cell lines. These findings suggest that AKT is frequently activated in MM cells, in part due to the downregulation of PTEN. Thus, the PI3K-AKT signaling pathway is a potential therapeutic target for MM.

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 90%

Activation of the PI3K-AKT pathway in human malignant mesothelioma cells

Suzuki

Murakami²,

Kawaguchi³

et al. 2009

Mol Med Rep

View full text Add to dashboard Cite

show abstract

“…To our knowledge, this is the first report of a homologous deletion of the PTEN tumor suppressor gene in MM. A previous analysis of the PTEN gene in 18 primary MMs did not uncover any mutations (Papp et al, 2001). In our series, however, loss of the PTEN gene was detected in one of nine human MM cell lines, and loss of PTEN protein expression was observed in two of 26 human MM specimens.…”

Section: Discussionmentioning

confidence: 90%

Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth

et al. 2005

View full text Add to dashboard Cite

Malignant mesotheliomas (MMs) are very aggressive tumors that respond poorly to standard chemotherapeutic approaches. The phosphatidylinositol 3-kinase (PI3K)/ AKT pathway has been implicated in tumor aggressiveness, in part by mediating cell survival and reducing sensitivity to chemotherapy. Using antibodies recognizing the phosphorylated/activated form of AKT kinases, we observed elevated phospho-AKT staining in 17 of 26 (65%) human MM specimens. In addition, AKT phosphorylation was consistently observed in MMs arising in asbestos-treated mice and in MM cell xenografts. Consistent with reports implicating hepatocyte growth factor (HGF)/Met receptor signaling in MM, all 14 human and murine MM cell lines had HGF-inducible AKT activity. One of nine human MM cell lines had elevated AKT activity under serum-starvation conditions, which was associated with a homozygous deletion of PTEN, the first reported in MM. Treatment of this cell line with the mTOR inhibitor rapamycin resulted in growth arrest in G1 phase. Treatment of MM cells with the PI3K inhibitor LY294002 in combination with cisplatin had greater efficacy in inhibiting cell proliferation and inducing apoptosis than either agent alone. Collectively, these data indicate that MMs frequently express elevated AKT activity, which may be targeted pharmacologically to enhance chemotherapeutic efficacy. These findings also suggest that mouse models of MM may be useful for future preclinical studies of pharmaceuticals targeting the PI3K/AKT pathway.

show abstract

“…It would be interesting to investigate the relationship between P16 and NF2 alterations from the viewpoint of the carcinogenesis of MPMs. Of note, mutations in other genes, including the P53, Ras, and RB genes (which have been found at high frequencies in other malignant tumors), are very rare in MPM [20,30,31].…”

Section: Discussionmentioning

confidence: 97%

Frequent p16 inactivation by homozygous deletion or methylation is associated with a poor prognosis in Japanese patients with pleural mesothelioma

et al. 2008

View full text Add to dashboard Cite

This study examined the p16 expression status and the P16 gene deletion and methylation status in specimens from Japanese patients with malignant pleural mesothelioma (MPM). Immunohistochemical staining for p16 protein and fluorescence in situ hybridization for the P16 gene were performed using specimens from 30 Japanese patients with primary MPM. The methylation status of the P16 gene was examined in 13 patients whose frozen tumor specimens were available using a methylation-specific PCR assay. Among the 30 patients, the loss of p16 protein expression was observed in 24 patients (80.0%). Twenty-one patients had homozygous deletions, and 9 patients retained the P16 gene. None of the patients with P16 homozygous deletions exhibited p16-positive expression, and 3 patients who retained the P16 gene did not exhibit p16-positive expression. Aberrant P16 methylation was present in two patients with an intact P16 gene but without p16 expression. These results suggest that either a homozygous deletion or methylation is responsible for P16 inactivation. Regarding the prognosis, patients with p16-negative expression had a significantly shorter survival time than those with p16-positive expression (P=0.040). Our study showed that P16 inactivation by homozygous deletions or methylation is a frequent event in Japanese patients with MPMs, relating to poor prognosis. Homozygous deletion is the major cause of P16 inactivation, but methylation also lead to the inactivation of P16 when the P16 alleles are retained.

show abstract

Mutational analysis of the PTEN/MMAC1 tumour suppressor gene in primary human malignant mesotheliomas

Cited by 10 publications

References 0 publications

Activation of the PI3K-AKT pathway in human malignant mesothelioma cells

Activation of the PI3K-AKT pathway in human malignant mesothelioma cells

Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth

Frequent p16 inactivation by homozygous deletion or methylation is associated with a poor prognosis in Japanese patients with pleural mesothelioma

Contact Info

Product

Resources

About