Inhibition of activated phosphatidylinositol 3-kinase/AKT pathway in malignant pleural mesothelioma leads to G1 cell cycle arrest

Our plain-English summary of Inhibition of activated phosphatidylinositol 3-kinase/AKT pathway in malignant pleural mesothelioma leads to G1 cell cycle arrest, by I. Mikami, F. Zhang, T. Hirata, et al (Oncology Reports, 2010).

The study

• Authors: I. Mikami, F. Zhang, T. Hirata, J. Okamoto, K. Koizumi, K. Shimizu, D. Jablons, B. He
• Journal: Oncology Reports
• Published: 2010;24(6):1677-81
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays pivotal roles in fundamental cellular functions including cell proliferation and cell survival. Its deregulation has been implicated in many types of human malignancies. We investigated the role of PI3K/AKT signaling pathway in human malignant pleural mesothelioma (MM). Here, we report that aberrant activation of the PI3K/AKT signaling pathway is associated with cell cycle progression in MM cells. Inhibition of the PI3K activity by its small molecule inhibitor LY294002 led to significant G1 cell cycle arrest and suppression of cell proliferation in all MM cell lines that we examined. In addition, we found that the protein level of p27Kip1 was up-regulated and the protein level of cyclin D1 was down-regulated following LY294002 treatment in those MM cell lines. However, no noticeable apoptosis induction was observed following 24 h of LY294002 treatment in those MM cell lines. These results confirm that the PI3K/AKT signaling pathway is aberrantly active and plays a critical role for the cell cycle progression in human MM cells.

In plain English

This was a laboratory study of human malignant pleural mesothelioma cells. It looked at a cell signalling pathway called PI3K/AKT. It did not study asbestos exposure. The authors used five mesothelioma cell lines (MS-1, REN, 211H, H28 and H2052) and 20 fresh tumour samples taken from patients during surgery. The activated form of the AKT protein was found in 19 of the 20 tumour samples. In all five cell lines, its level rose after the cells were given serum. The cells were then treated with LY294002, a drug that blocks PI3K, at 20 micromolar. Compared with control cells, all five lines showed a significant halt in an early growth phase of the cell cycle (called G1) and significantly less cell growth. After treatment, the protein p27Kip1 increased and the protein cyclin D1 decreased. The authors reported no significant cell death (apoptosis) within 24 hours of treatment. The authors concluded that the PI3K/AKT pathway regulates cell cycle progression in mesothelioma cells, and that their findings support the pathway as a treatment target.

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 human mesothelioma cell lines and surgical tumour samples
• Who was studied: Five human malignant mesothelioma cell lines (MS-1, REN, 211H, H28, H2052) and 20 fresh primary malignant mesothelioma tissue samples from patients undergoing surgical resection (University of California, San Francisco)
• Exposure: No asbestos exposure was studied. Cells were treated with the PI3K inhibitor LY294002 (mainly 20 micromolar) or with DMSO as a control.
• Main results:
  • Phosphorylated (activated) AKT was found in 19 of 20 fresh mesothelioma tissue samples (95%)
  • In all five cell lines, phosphorylated AKT increased after serum treatment compared with serum-free cells
  • In 211H cells, LY294002 at 5 to 40 micromolar strongly reduced phosphorylated AKT
  • In all five cell lines, LY294002 (20 micromolar, 24 h) caused significant G1 cell cycle arrest compared with DMSO-treated cells
  • In all five cell lines, LY294002 significantly inhibited cell proliferation compared with DMSO-treated cells
  • After LY294002 treatment, p27Kip1 protein was significantly increased in the mesothelioma cell lines
  • After LY294002 treatment, cyclin D1 protein was significantly decreased in the treated cell lines
  • No significant apoptosis was seen in the cell lines after up to 24 h of LY294002 treatment
• The authors' conclusion: The authors concluded that the PI3K/AKT pathway is frequently activated in human mesothelioma and plays a role in cell cycle progression, and that their findings support this pathway as a therapeutic target.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Apoptosis.

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• Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy — B. Fischer, C. Frei, et al. (2012)
• Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors — N. Echeverry, G. Ziltener, et al. (2015)
• Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways — C.W. Menges, E. Sementino, et al. (2012)
• Synergistic anti-cancer effects of resveratrol and chemotherapeutic agent clofarabine against human malignant mesothelioma MSTO-211H cells — Y.J. Lee, Y.J. Lee, et al. (2013)

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