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

Our plain-English summary of Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth, by D.A. Altomare, H. You, G.H. Xiao, et al (Oncogene, 2005).

The study

• Authors: D.A. Altomare, H. You, G.H. Xiao, M.E. Ramos-Nino, K.L. Skele, A. De Rienzo, S.C. Jhanwar, B.T. Mossman, A.B. Kane, J.R. Testa
• Journal: Oncogene
• Published: 2005;24(40):6080-9
• Cited by: 135 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

In plain English

This laboratory study asked whether AKT, a protein that helps cells survive and grow, is switched on in malignant mesothelioma. The authors stained 26 human mesothelioma tumor samples and found strong staining for the active form of AKT in 17 of 26 (65%). Active AKT was also seen in mesothelioma tumors that developed in mice injected in the abdomen with crocidolite asbestos. A growth factor called HGF raised AKT activity in all 14 human and mouse mesothelioma cell lines tested. One of nine human cell lines, called M43, was missing part of the PTEN gene, which normally holds AKT in check. In cell lines, the drug rapamycin raised the share of M43 cells stalled in an early growth phase by about 30%. Combining the AKT-pathway blocker LY294002 with the chemotherapy drug cisplatin slowed cell growth more than either drug alone, by 2.4-fold in M43 cells and 1.4-fold in a second line. The authors concluded that mesotheliomas frequently have raised AKT activity, which may be targeted with drugs to make chemotherapy work better.

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 study using human mesothelioma tumor samples, mouse models of mesothelioma, and human and mouse mesothelioma cell lines
• Who was studied: Tumor samples from 26 patients with malignant mesothelioma: 19 on a tissue microarray from Fox Chase Cancer Center and 7 from the Cooperative Human Tissue Network. The study also used mice, five mouse mesothelioma cell lines and nine human mesothelioma cell lines.
• Exposure: Crocidolite asbestos was injected into the abdomen of mice to produce mesothelioma: eight injections, one every 21 days, totalling 3.2 mg per mouse. Asbestos exposure of the human patients is not reported. Cell lines were treated with the drugs LY294002, rapamycin and cisplatin.
• Main results:
  • Human tumor samples: 17 of 26 (65%) showed strong staining for active (phosphorylated) AKT.
  • Human tumor samples: staining for active mTOR, a protein further along the AKT pathway, matched active-AKT staining in 24 of 26 (92%) cases.
  • Mice: strong active-AKT staining was seen in mesothelioma tumor nodules in the abdominal wall of mice injected with crocidolite asbestos.
  • Cell lines: all 14 human and mouse mesothelioma cell lines showed AKT activity that could be raised by the growth factor HGF.
  • Loss of the PTEN gene was found in one of nine human mesothelioma cell lines (M43). Loss of PTEN protein was found in two of 26 human tumor samples.
  • M43 cells: rapamycin treatment for 48 hours gave a 30% increase in the average percent of cells in the G1 (early growth) phase compared with placebo (P = 0.016).
  • M43 cells: 48 hours of LY294002 gave a 3.3-fold increase in dying (sub-G1) cells compared with placebo (P = 0.013).
  • M43 and M17 cell lines: compared with either drug alone, LY294002 plus cisplatin inhibited cell growth 2.4-fold in M43 cells and 1.4-fold in M17 cells.
  • M43 cells: in two tests, LY294002 plus cisplatin was more effective at triggering cell death (apoptosis) than either drug alone.
• The authors' conclusion: The authors concluded that mesotheliomas frequently have raised AKT activity, which may be targeted with drugs to make chemotherapy work better.
• Limitations the authors state:
  • M43 cells, the line used for most drug tests, had not been tested for their ability to form tumors in mice.
  • The study used only established mesothelioma cell lines, because cell lines from early, pre-cancerous mesothelial lesions are not available.
  • The study did not explore all the possible ways AKT could be switched on in mesothelioma.
  • Cells were examined at 48 hours, so rapamycin might cause more cell death with longer exposure.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Chemotherapy, Homozygous Deletion, Cisplatin, Apoptosis.

Related studies

• SV40-dependent AKT activity drives mesothelial cell transformation after asbestos exposure — P. Cacciotti, D. Barbone, et al. (2005)
• Combined treatment with cisplatin and sirolimus to enhance cell death in human mesothelioma — M.L. Hartman, J.M. Esposito, et al. (2010)
• The Wnt regulator SFRP4 inhibits mesothelioma cell proliferation, migration, and antagonizes Wnt3a via its netrin-like domain — V. Perumal, A.M. Dharmarajan, et al. (2017)
• beta1-integrin mediates asbestos-induced phosphorylation of AKT and ERK1/2 in a rat pleural mesothelial cell line — A. Berken, J. Abel, et al. (2003)
• Coactivation of receptor tyrosine kinases in malignant mesothelioma as a rationale for combination targeted therapy — M. Brevet, S. Shimizu, et al. (2011)
• ADP sensitizes ZL55 cells to the activity of cisplatin — A. Muscella, L.G. Cossa, et al. (2019)

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