Modulation of p53, ErbB1, ErbB2, and Raf-1 Expression in Lung Cancer Cells by Depsipeptide FR901228
Abstract
BACKGROUND: Histone deacetylases (HDACs) modulate chromatin structure by regulating acetylation of core histone proteins. HDAC inhibitors, such as depsipeptide FR901228 (FK228), induce growth arrest and apoptosis in a variety of human cancer cells by mechanisms that cannot be attributed solely to histone acetylation. This study evaluated the mechanisms by which FK228 mediates apoptosis in non-small-cell lung cancer (NSCLC) cells. METHODS: Proliferation and apoptosis were assessed in a panel of NSCLC cell lines that vary in the expression of the growth-regulating proteins p53, pRb, and K-Ras treated with a clinically relevant dose of FK228 (25 ng/mL). Western blot and immunoprecipitation techniques were used to analyze expression of cell-cycle proteins (cyclin A, cyclin E, p53, and p21), signaling-related proteins (ErbB1, ErbB2, and Raf-1), activity of extracellular signal-regulated kinase 1 and 2 (ERK1/2), binding of mutant p53 and Raf-1 to heat shock protein (Hsp)90, and acetylation of Hsp90. RESULTS: FK228 treatment inhibited growth and induced apoptosis in NSCLC cells expressing wild-type or mutant p53. FK228 treatment led to altered expression of cyclin A, cyclin E, and p21, and to reduced expression of mutant, but not wild-type, p53. FK228-treated cells also were depleted of ErbB1, ErbB2, and Raf-1 proteins, and exhibited lower ERK1/2 activity. FK228 treatment also inhibited the binding of mutant p53 and Raf-1 to Hsp90; this inhibition was associated with acetylation of Hsp90. CONCLUSIONS: FK228 depletes the levels of several oncoproteins that are normally stabilized by binding to Hsp90 in cancer cells. The resulting ability of FK228 to diminish signal transduction via pathways involving Raf-1 and ERK may contribute to the potency and specificity of this novel antitumor agent.
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TSA induces acetylation of Hsp90 in eukaryotes.
“To further investigate the potential of acetylation to inhibit Hsp90 function, we used trichostatin A (TSA), which was shown to induce acetylation of Hsp90 in eukaryotes (17–20).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [20]
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- Authors
- Yu, X.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Yu, X.
- ORCID
- Yu, X.
- Venue
- CancerSpectrum Knowledge Environment
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-04-03
- Volume
- 94
- Issue
- 7
- Pages
- 504-513
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- OpenAlex
- W2108230631
- Cited by
- 360
- References
- 53
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 6 · 2017: 8 · 2016: 4 · 2015: 14 · 2014: 17 · 2013: 13 · 2012: 20
- FWCI
- 10.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- romidepsin, histone deacetylase inhibitors, non-small cell lung cancer, apoptosis, p53, EGF receptor, ERBB2, Raf-1, HSP90, ERK signaling, cyclin A, cyclin E, p21, KRAS, retinoblastoma protein
- MeSH terms
- Anti-Bacterial Agents, Antibiotics, Antineoplastic, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Peptides, Cyclic, Precipitin Tests, RNA, Messenger, Tumor Cells, Cultured, Blotting, Northern, Blotting, Western, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Cell Cycle Proteins, HSP90 Heat-Shock Proteins, Proto-Oncogene Proteins c-raf, Mitogen-Activated Protein Kinase 1, Depsipeptides, ErbB Receptors
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