Mesothelioma cell proliferation through autocrine activation of PDGF-ββ receptor

Our plain-English summary of Mesothelioma cell proliferation through autocrine activation of PDGF-ββ receptor, by M. Honda, T. Kanno, Y. Fujita, et al (Cellular Physiology and Biochemistry, 2012).

The study

• Authors: M. Honda, T. Kanno, Y. Fujita, A. Gotoh, T. Nakano, T. Nishizaki
• Journal: Cellular Physiology and Biochemistry
• Published: 2012;29(5-6):667-74
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background/aims: Growth factors play a critical role in proliferation for a variety of cancer cells. The present study was conducted to understand the signaling cascades underlying PDGF-D/PDGF-ββ receptor-mediated proliferation of mesothelioma cells.

Methods: Cell growth and cell cycle were analyzed in human non-malignant Met5A cells and malignant mesothelioma cells such as MSTO-211H, NCI-H28, NCI-H2052, and NCI-H2452 cells.

Results: Growth of all the cells used here was not affected by PDGF-D, regardless of concentrations (1-30 ng/ml) or treatment time (48-72 h). Spontaneous growth of those cells was significantly inhibited by knocking-down PDGFD or PDGF-ββ receptor, without affecting cell cycling. The cell growth was significantly inhibited by the Akt inhibitor MK2206 and the ROCK inhibitor Y27632 for all the cell types, by the PDK1 inhibitor BX912 for NCI-H28 cells alone, and by the Rac1 inhibitor NSC23766 for NCI-H2052 cells alone, while the PI3 kinase inhibitor wortmannin had no effect. The cell growth, alternatively, was significantly attenuated by MAP kinase kinase inhibitor PD98059 or the ERK1/2 inhibitor FR180204 for all the cell types.

Conclusion: The results of the present study show that PDGF-D promotes mesothelioma cell proliferation by targeting ROCK or MAP kinase through autocrine activation of PDGF-ββ receptor.

Copyright © 2012 S. Karger AG, Basel.

In plain English

This was a laboratory study of human cells grown in culture. No people and no asbestos exposure were studied. The authors used one non-malignant cell line (Met5A) and four malignant mesothelioma cell lines (MSTO-211H, NCI-H28, NCI-H2052 and NCI-H2452). They asked how a growth factor called PDGF-D and its receptor, the PDGF-ββ receptor, relate to cell growth. Adding PDGF-D to the cells did not change growth in any of the five lines. When the cells' own PDGF-D or the receptor was knocked down, growth fell in all five lines, including the non-malignant one. Cell-cycle phases were checked only after receptor knockdown, and they were unchanged. Drugs blocking Akt, ROCK, MEK or ERK1/2 reduced growth in all lines. A PI3 kinase blocker (wortmannin) had no effect. The malignant lines expressed more uPA mRNA than Met5A cells. The authors concluded that PDGF-D promotes mesothelioma cell proliferation through autocrine activation of the PDGF-ββ receptor. In their view this works by activating ROCK, through a route independent of the PI3 kinase/PDK1/Akt/Rac1 pathway, or MAP kinase, possibly along a Ras/Raf/MEKK/MEK route.

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) experiments on purchased, cultured human cell lines
• Who was studied: Five human cell lines: non-malignant Met5A cells and the malignant mesothelioma cell lines MSTO-211H, NCI-H28, NCI-H2052 and NCI-H2452. No human subjects.
• Exposure: No asbestos or fiber exposure was studied. The cells were treated with added PDGF-D. PDGF-D or the PDGF-ββ receptor was knocked down with siRNA. The cells were also exposed to signaling inhibitors, each for 48 h: wortmannin (10 μM), BX912 (100 nM), MK2206 (5 μM), NSC23766 (1 μM), Y27632 (10 μM), PD98059 (50 μM) and FR180204 (10 μM).
• Main results:
  • Adding PDGF-D at 1 to 30 ng/ml for 48 h, or at 10 ng/ml for 48 to 72 h, did not affect growth of any of the five cell lines.
  • Knocking down PDGF-D or the PDGF-ββ receptor reduced spontaneous growth in all five cell lines, including non-malignant Met5A.
  • The cell cycle was analyzed only after knockdown of the PDGF-ββ receptor. Receptor knockdown did not change any phase of the cell cycle in any of the cell lines.
  • The Akt inhibitor MK2206 (5 μM) and the ROCK inhibitor Y27632 (10 μM) significantly inhibited growth in all cell lines. Y27632 had the strongest effect.
  • The PDK1 inhibitor BX912 reduced growth only in NCI-H28 cells. The Rac1 inhibitor NSC23766 reduced growth only in NCI-H2052 cells.
  • The PI3 kinase inhibitor wortmannin did not inhibit growth in any cell line.
  • The MEK inhibitor PD98059 (50 μM) and the ERK1/2 inhibitor FR180204 (10 μM) significantly reduced growth in all cell lines.
  • The four malignant mesothelioma cell lines expressed more uPA mRNA than non-malignant Met5A cells. PAI-1 mRNA did not differ between malignant and non-malignant cells. No statistical test is reported for this comparison.
• The authors' conclusion: The authors concluded that PDGF-D promotes mesothelioma cell proliferation through autocrine activation of the PDGF-ββ receptor. In their view this happens either by activating ROCK, through a pathway independent of the PI3 kinase/PDK1/Akt/Rac1 (Cdc42) axis, or by activating MAP kinase, possibly along a Ras/Raf/MEKK/MEK axis.
• Limitations the authors state:
  • The authors did not examine whether MEK and ERK are activated through the Ras/Raf/MEKK pathway downstream of the PDGF-ββ receptor.
  • The authors state that how ROCK is activated in mesothelioma cells is still unknown.

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, Platelet-Derived Growth Factor (PDGF), Malignant Mesothelioma.

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