A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species
Published version of a preprint
Abstract
The RAS/BRAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway is emerging as a key modulator of melanoma initiation and progression. However, a variety of clinical studies indicate that inhibiting the MAPK pathway is insufficient per se to effectively kill melanoma cells. Here, we report on a genetic and pharmacologic approach to identify survival factors responsible for the resistance of melanoma cells to MEK/ERK antagonists. In addition, we describe a new tumor cell–selective means to bypass this resistance in vitro and in vivo. By generating a panel of isogenic cell lines with specific defects in the apoptotic machinery, we found that the ability of melanoma cells to survive in the absence of functional MEK relies on an ERK-independent expression of the antiapoptotic factor Mcl-1 (and to a lesser extent, Bcl-xL and Bcl-2). Using computer-based modeling, we developed a novel Bcl-2 homology domain 3 (BH3) mimetic. This compound, named TW-37, is the first rationally designed small molecule with high affinity for Mcl-1, Bcl-xL, and Bcl-2. Mechanistic analyses of the mode of action of TW-37 showed a synergistic tumor cell killing in the presence of MEK inhibitors. Importantly, TW-37 unveiled an unexpected role of the MAPK pathway in the control of reactive oxygen species (ROS). This function was critical to prevent the activation of proapoptotic functions of p53 in melanoma cells, but surprisingly, it was dispensable for normal melanocytes. Our results suggest that this MAPK-dependent ROS/p53 feedback loop is a point of vulnerability of melanoma cells that can be exploited for rational drug design. (Cancer Res 2006; 66(23): 11348-59)
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TPC-1 cells were stably transfected with shRNA-p53 or scrambled sequence control shRNA.
“The DePTC cells (TPC-1) were stably transfected with lentiviral vectors expressing shRNA-p53 corresponding to p53 nucleotides 611-629 [52] or scrambled sequence control shRNA (GenePharma, 20 Suzhou, China) for 3 days and then selected with 1.0 μg/ml puromycin (sigma, Shanghai, China) for 2 weeks.”
From Restoration of p53 using the novel MDM2-p53 antagonist APG115 suppresses dedifferentiated papillary thyroid cancer cells (2017) · cites this paper as [52]
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- Authors
- Verhaegen, M., Bauer, J. A., Martín de la Vega, C., Wang, G., Wolter, K. G., Brenner, J. C., Nikolovska-Coleska, Z., Bengtson, A., Nair, R., Elder, J. T., Van Brocklin, M., Carey, T. E., Bradford, C. R., Wang, S., & Soengas, M. S.
- Affiliations
- University of Michigan (US)
- 1Dermatology, Departments of
- 4Otolaryngology, and
- 2Pharmacology,
- U-M Rogel Cancer Center (US)
- 7Van Andel Research Institute, Grand Rapids, Michigan
- ORCID
- Venue
- Cancer Research
- Published
- 2006-12-01
- Volume
- 66
- Issue
- 23
- Pages
- 11348-11359
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2109351911
- Cited by
- 140
- References
- 66
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 6 · 2021: 6 · 2020: 1 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 5 · 2015: 3 · 2014: 12 · 2013: 7 · 2012: 6
- FWCI
- 7.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (5P30 CA 46592, R01CA107237, CA83087, R01CA083087, U19CA113317, P30CA046592)
- National Institute on Deafness and Other Communication Disorders (DC-00011)
- National Institute of General Medical Sciences (T32-GM-07767, T32GM007767)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR042742, R01AR050511, R01AR042742, AR050511)
- National Institute of Dental and Craniofacial Research (R01DE013346, DE-13346)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- melanoma, BH3 mimetics, TW-37, Mcl-1, Bcl-2, Bcl-xL, MEK/ERK inhibitor, MAPK signaling, p53, reactive oxygen species, apoptosis, drug resistance, isogenic cell lines, melanocytes, combination therapy
- MeSH terms
- Animals, Benzamides, Butadienes, Cell Survival, Cells, Cultured, Dose-Response Relationship, Drug, Drug Synergism, Humans, Melanoma, Mice, Nude, Microscopy, Fluorescence, Nitriles, Sulfones, Molecular Structure, Tumor Suppressor Protein p53, Apoptosis, Reactive Oxygen Species, Proto-Oncogene Proteins c-bcl-2, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, RNA Interference, Cell Line, Tumor, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mice
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