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/p27Kip1 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.
Highlights
Breast cancer (BC) is the most frequently diagnosed cancer in North America and figures among the leading causes of cancer deaths in women worldwide [1]
To elucidate the involvement of internal/nuclear G protein-coupled receptors (GPCRs), B2R, in triple-negative breast cancer (TNBC) tumorogenesis, we designed and/or characterized newly kinin CPB2RAs that were tested as anticancer agents
We present novel data demonstrating 1) strong constitutive intracellular/nuclear B2R localization in TNBC cells and tissue specimens; 2) that CP-B2RAs can interact with nuclear B2R sites and exhibit potent anticancer activities in cultured TNBC cells; a common mechanism underlying their anticancer effects may involve induction of G1phase growth arrest and apoptosis through activation of p38kinase/p27Kip1 pathways; and 3) that targeting intracellular B2R using CP-B2RAs is more effective than currently utilized chemotherapy while acting synergistically or additively with others to enhance their mutual cytocidal effects against TNBC cells
Summary
Breast cancer (BC) is the most frequently diagnosed cancer in North America and figures among the leading causes of cancer deaths in women worldwide [1] This situation remains true despite improvements in screening and treatment. Non-invasive forms of BC most often originate from the galactophorous ducts and lobules www.impactjournals.com/oncotarget (the milk-producing glands) and are classified as ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS). They are generally benign tumors accounting for approximately 20% and 1% of all newly diagnosed BC cases, respectively [2]. Available treatments include some combination of surgery, radiation, chemotherapy, hormonal therapy, and targeted therapies including the use of monoclonal antibodies (e.g. trastuzumab; Herceptin®) notably for HER-2-positive patients [3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
