Abstract
We reported previously that Bcl-2 is paradoxically down-regulated in paclitaxel-resistant cancer cells. We reveal here that paclitaxel directly targets Bcl-2 in the loop domain, thereby facilitating the initiation of apoptosis. Molecular modeling revealed an extraordinary similarity between the paclitaxel binding sites in Bcl-2 and beta-tubulin, leading us to speculate that paclitaxel could be mimetic of an endogenous peptide ligand, which binds both proteins. We tested the hypothesis that paclitaxel mimics Nur77, which, like paclitaxel, changes the function of Bcl-2. This premise was confirmed by Nur77 interacting with both paclitaxel targets (Bcl-2 and beta-tubulin) and a peptide sequence mimicking the Nur77 structural region, thus reproducing the paclitaxel-like effects of tubulin polymerization and opening the permeability transition pore channel in mitochondria. This discovery could help in the development of novel anticancer agents with nontaxane skeleton as well as in identifying the clinical subsets responsive to paclitaxel-based therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / chemistry
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Antineoplastic Agents, Phytogenic / metabolism
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects
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Binding Sites
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Cells, Cultured
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism*
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DNA-Binding Proteins / pharmacology
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Female
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Humans
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Mice
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Mice, Nude
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Mitochondria / drug effects
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Mitochondria / metabolism
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Models, Molecular
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Molecular Mimicry
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Neoplasms / drug therapy
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Paclitaxel / chemistry
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Paclitaxel / metabolism*
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Paclitaxel / pharmacology
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism
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Protein Binding
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Proto-Oncogene Proteins c-bcl-2 / chemistry
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Receptors, Steroid / chemistry
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Receptors, Steroid / metabolism*
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Tubulin / metabolism
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Tubulin Modulators / chemistry
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Tubulin Modulators / metabolism
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Tubulin Modulators / pharmacology
Substances
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Antineoplastic Agents, Phytogenic
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DNA-Binding Proteins
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NR4A1 protein, human
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Nr4a1 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Peptide Fragments
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Steroid
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Tubulin
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Tubulin Modulators
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Paclitaxel