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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Molecular Cancer 1/2012

Targeting filamin A reduces K-RAS–induced lung adenocarcinomas and endothelial response to tumor growth in mice

Zeitschrift:
Molecular Cancer > Ausgabe 1/2012
Autoren:
Rajesh K Nallapalli, Mohamed X Ibrahim, Alex X Zhou, Sashidar Bandaru, Sai Naresh Sunkara, Björn Redfors, David Pazooki, Yin Zhang, Jan Borén, Yihai Cao, Martin O Bergo, Levent M Akyürek
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1476-4598-11-50) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

RKN, MOB, LMA designed research; RKN, MXI, SB, SSN, BR, YZ performed research; RKN, MXI, AXZ, SB, DP, JB, YC, MOB, LMA analysed the data; RKN, MOB, LMA wrote the paper. All authors read and approved the final manuscript.

Abstract

Background

Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro.

Methods

First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells.

Results

Knockout of Flna significantly reduced K-RAS–induced lung tumor formation and the proliferation of oncogenic K-RAS–expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors.

Conclusions

We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics.
Zusatzmaterial
Authors’ original file for figure 1
12943_2012_1020_MOESM1_ESM.pdf
Authors’ original file for figure 2
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Authors’ original file for figure 3
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Authors’ original file for figure 4
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Authors’ original file for figure 5
12943_2012_1020_MOESM5_ESM.pdf
Literatur
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