Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77.
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.
Ferlini
Cristiano
C
Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy. cferlini@rm.unicatt.it
Cicchillitti
Lucia
L
Raspaglio
Giuseppina
G
Bartollino
Silvia
S
Cimitan
Samanta
S
Bertucci
Carlo
C
Mozzetti
Simona
S
Gallo
Daniela
D
Persico
Marco
M
Fattorusso
Caterina
C
Campiani
Giuseppe
G
Scambia
Giovanni
G
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D009369:Neoplasms / Q000188:drug therapy; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D011987:Receptors, Steroid / Q000737:chemistry / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D011987:Receptors, Steroid; D014404:Tubulin; D050257:Tubulin Modulators; D017239:Paclitaxel