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Regulation of adhesion and growth of fibrosarcoma cells by NF-kappa B RelA involves transforming growth factor beta
J R Perez1, K A Higgins-Sochaski, J Y Maltese
1Division of Oncology, Roche Research Center, Hoffman-La Roche, Inc., Nutley, New Jersey 07110.
Abstract:
The NF-kappa B transcription factor is a pleiotropic activator that participates in the induction of a wide variety of cellular genes. Antisense oligomer inhibition of the RelA subunit of NF-kappa B results in a block of cellular adhesion and inhibition of tumor cell growth. Investigation of the molecular basis for these effects showed that in vitro inhibition of the growth of transformed fibroblasts by relA antisense oligonucleotides can be reversed by the parental-cell-conditioned medium. Cytokine profile analysis of these cells treated with relA antisense oligonucleotides revealed inhibition of transforming growth factor beta 1 (TGF-beta 1 to the transformed fibroblasts reversed the inhibitory effects of relA antisense oligomers on soft agar colony formation and cell adhesion to the substratum. Direct inhibition of TGF-beta 1 expression by antisense phosphorothioates to TGF-beta 1 mimicked the in vitro effects of blocking cell adhesion that are elicited by antisense relA oligomers. These results may explain the in vitro effects of relA antisense oligomers on fibrosarcoma cell growth and adhesion.
Insights
Inhibiting the RelA subunit of NF-kappa B blocks tumor cell growth and adhesion, partly by reducing transforming growth factor beta 1 (TGF-beta 1). Restoring TGF-beta 1 reverses these effects, highlighting its role in fibrosarcoma progression.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Nuclear factor kappa B (NF-kappa B) is a transcription factor regulating numerous cellular genes.
- Inhibition of the RelA subunit of NF-kappa B using antisense oligomers has been shown to impede tumor cell growth and adhesion.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the effects of RelA inhibition on cell adhesion and growth.
- To determine the role of transforming growth factor beta 1 (TGF-beta 1) in the observed phenotypes.
Main Methods:
- Utilized antisense oligonucleotides targeting the RelA subunit of NF-kappa B in transformed fibroblasts.
- Analyzed cell adhesion, soft agar colony formation, and cytokine profiles.
- Investigated the effects of conditioned medium and direct TGF-beta 1 inhibition using antisense phosphorothioates.
Main Results:
- RelA antisense oligomer treatment inhibited transformed fibroblast growth and adhesion.
- These inhibitory effects were reversed by parental-cell-conditioned medium.
- Cytokine analysis revealed that relA antisense treatment suppressed TGF-beta 1 expression.
- Direct inhibition of TGF-beta 1 mimicked the effects of relA antisense oligomers on cell adhesion and growth.
Conclusions:
- TGF-beta 1 plays a significant role in mediating the effects of RelA inhibition on fibrosarcoma cell adhesion and growth.
- Targeting RelA or TGF-beta 1 may represent a therapeutic strategy for fibrosarcoma.
- The findings elucidate the molecular interplay between NF-kappa B signaling and TGF-beta 1 in cancer progression.