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

Our plain-English summary of Activation of the PI3K-AKT pathway in human malignant mesothelioma cells, by Y. Suzuki, H. Murakami, K. Kawaguchi, et al (Molecular Medicine Reports, 2009).

The study

• Authors: Y. Suzuki, H. Murakami, K. Kawaguchi, T. Tanigushi, M. Fujii, K. Shinjo, Y. Kondo, H. Osada, K. Shimokata, Y. Horio, Y. Hasegawa, T. Hida, Y. Sekido
• Journal: Molecular Medicine Reports
• Published: 2009;2(2):181-8
• Cited by: 46 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This was a laboratory study of 21 malignant mesothelioma (MM) cell lines, 15 of them established by the authors from Japanese patients, compared with MeT-5A, an immortalized line from normal mesothelial cells. It did not study asbestos exposure. The authors examined a cell-signaling pathway called PI3K-AKT. In 13 (62%) of the 21 MM lines, AKT was activated when the cells were grown without serum. Activated AKT was undetectable in the other 8 lines and in MeT-5A. No mutations were found in the PIK3CA or LKB1 genes. Two lines, ACC-MESO-1 and Y-MESO-25, had a deletion of both copies of part of the PTEN gene: about 40 kb including exon 2 in the first, and 7.7 kb including exon 1 in the second. Eleven other lines had low PTEN protein. Putting working PTEN back into the two PTEN-deleted lines reduced the number of colonies they formed, while a non-working PTEN version did not. Some lines with low PTEN showed no obvious AKT activation. The authors concluded that AKT is frequently activated in MM cells, in part due to reduced PTEN. They noted they did not study loss of heterozygosity or methylation of PTEN.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of cell lines: gene mutation and expression analyses
• Who was studied: 21 malignant mesothelioma cell lines, 15 of them established by the authors' laboratory in Japan from Japanese patients, plus one immortalized normal mesothelial cell line (MeT-5A) used for comparison
• Exposure: No asbestos exposure was studied. Asbestos is mentioned only as background. The study examined the PI3K-AKT signaling pathway and the PTEN, PIK3CA and LKB1 genes in mesothelioma cells.
• Main results:
  • AKT was activated (phosphorylated) in 13 (62%) of the 21 MM cell lines under serum-starved conditions: at a high level in 6 and a mid level in 7. Activated AKT was undetectable in the other 8 MM lines and in MeT-5A.
  • No mutations were found in the PIK3CA or LKB1 genes in the MM cell lines.
  • Two cell lines had a homozygous deletion of PTEN, and 11 cell lines had low PTEN protein compared with MeT-5A.
  • Ten other cell lines had PTEN mRNA at less than half the MeT-5A level. Seven lines were low at both the mRNA and protein level.
  • In ACC-MESO-1, the PTEN deletion was about 40 kb and included exon 2.
  • In Y-MESO-25, the PTEN deletion was 7.7 kb and included the promoter region and exon 1.
  • The original tumor sample from which Y-MESO-25 was grown also showed defective PTEN expression on immunohistochemistry.
  • Re-introducing PTEN into the two PTEN-deleted lines (ACC-MESO-1 and Y-MESO-25) suppressed colony formation.
  • In the colony formation assay, wild-type PTEN reduced the number of colonies, but the H123Y mutant form did not.
  • A dominant negative form of AKT also inhibited colony formation.
  • Some lines with low PTEN at both the mRNA and protein level did not show obvious AKT activation.
• The authors' conclusion: The authors concluded that AKT is frequently activated in MM cells, in part due to downregulation of PTEN.
• Limitations the authors state:
  • The authors did not study loss of heterozygosity (LOH) or methylation of the PTEN gene, which they suggested might explain the low PTEN levels.

Topics

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Neoplasm, Asbestos Exposure, Mesothelial Cells.

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