Targeting intracellular B2 receptors using novel cell-penetrating antagonists to arrest growth and induce apoptosis in human triple-negative breast cancer
Bibliographic record
Abstract
// Céléna Dubuc 1, 2, * , Martin Savard 1, 2, * , Veronica Bovenzi 1, 2, * , Andrée Lessard 3 , Audrey Fortier 1, 2 , Jérôme Côté 1, 2 , Witold Neugebauer 1, 2 , Flavio Rizzolio 4, 5 , Sameh Geha 6 , Antonio Giordano 4 , Sylvain Chemtob 7 and Fernand Gobeil 1, 2 1 Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada 2 Institute of Pharmacology, Université de Sherbrooke, Sherbrooke, Québec, Canada 3 Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, United States 4 Department of Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, USA 5 Dipartimento di Scienze Molecolari e Nanosistemi, Università Ca' Foscari Venezia, Mestre-Venezia, Italy 6 Department of Pathology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada 7 Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, Québec, Canada * Joint first authorship Correspondence to: Fernand Gobeil, email: fernand.gobeil@usherbrooke.ca Keywords: triple-negative breast cancer; kinins; cell-permeable antagonist; nuclear GPCRs; intracrine signaling Received: June 08, 2017 Accepted: October 02, 2017 Published: January 05, 2018 ABSTRACT G protein-coupled receptors (GPCRs) are integral cell-surface proteins having a central role in tumor growth and metastasis. However, several GPCRs retain an atypical intracellular/nuclear location in various types of cancer. The pathological significance of this is currently unknown. Here we extend this observation by showing that the bradykinin B2R (BK-B2R) is nuclearly expressed in the human triple-negative breast cancer (TNBC) cell line MDA-MB-231 and in human clinical specimens of TNBC. We posited that these “nuclearized” receptors could be involved in oncogenic signaling linked to aberrant growth and survival maintenance of TNBC. We used cell-penetrating BK-B2R antagonists, including FR173657 and novel transducible, cell-permeable forms of the peptide B2R antagonist HOE 140 (NG68, NG134) to demonstrate their superior efficacy over impermeable ones (HOE 140), in blocking proliferation and promoting apoptosis of MDA-MB-231 cells. Some showed an even greater antineoplastic activity over conventional chemotherapeutic drugs in vitro . The cell-permeable B2R antagonists had less to no anticancer effects on B2R shRNA-knockdown or non-B2R expressing (COS-1) cells, indicating specificity in their action. Possible mechanisms of their anticancer effects may involve activation of p38kinase/p27 Kip1 pathways. Together, our data support the existence of a possible intracrine signaling pathway via internal/nuclear B2R, critical for the growth of TNBC cells, and identify new chemical entities that enable to target the corresponding intracellular GPCRs.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".