The Orphan GPR50 Receptor Regulates the Aggressiveness of Breast Cancer Stem-like Cells via Targeting the NF-kB Signaling Pathway

Polash Kumar Biswas; Sang Rok Park; Jongyub An; Kyung Min Lim; Ahmed Abdal Dayem; Kwonwoo Song; Hye Yeon Choi; Yujin Choi; Kyoung Sik Park; Hyun Jin Shin; Aram Kim; Minchan Gil; Subbroto Kumar Saha; Ssang-Goo Cho

doi:10.3390/ijms24032804

The Orphan GPR50 Receptor Regulates the Aggressiveness of Breast Cancer Stem-like Cells via Targeting the NF-kB Signaling Pathway

Int J Mol Sci. 2023 Feb 1;24(3):2804. doi: 10.3390/ijms24032804.

Authors

Affiliations

¹ Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
² Division of Biological Sciences, University of Montana, Missoula, MT 59812, USA.
³ Department of Surgery, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05029, Republic of Korea.
⁴ Department of Ophthalmology, Research Institute of Medical Science, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05029, Republic of Korea.
⁵ Department of Urology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05029, Republic of Korea.

Abstract

The expression of GPR50 in CSLC and several breast cancer cell lines was assessed by RT-PCR and online platform (UALCAN, GEPIA, and R2 gene analysis). The role of GPR50 in driving CSLC, sphere formation, cell proliferation, and migration was performed using shGPR50 gene knockdown, and the role of GPR50-regulated signaling pathways was examined by Western blotting and Luciferase Assay. Herein, we confirmed that the expression of G protein-coupled receptor 50 (GPR50) in cancer stem-like cells (CSLC) is higher than that in other cancer cells. We examined that the knockdown of GPR50 in CSLC led to decreased cancer properties, such as sphere formation, cell proliferation, migration, and stemness. GPR50 silencing downregulates NF-kB signaling, which is involved in sphere formation and aggressiveness of CSLC. In addition, we demonstrated that GPR50 also regulates ADAM-17 activity by activating NOTCH signaling pathways through the AKT/SP1 axis in CSLC. Overall, we demonstrated a novel GPR50-mediated regulation of the NF-κB-Notch signaling pathway, which can provide insights into CSLC progression and prognosis, and NF-κB-NOTCH-based CSLC treatment strategies.

Keywords: ADAM17; GPR50; NF-kB; Notch; breast cancer stem cell (BCSC).

MeSH terms

Breast Neoplasms* / genetics
Cell Line, Tumor
Female
Humans
NF-kappa B* / metabolism
Nerve Tissue Proteins / metabolism
Receptors, G-Protein-Coupled / genetics
Signal Transduction

Substances

NF-kappa B
Receptors, G-Protein-Coupled
GPR50 protein, human
Nerve Tissue Proteins

Grants and funding

This study was supported by a grant from the National Research Foundation (NRF) funded by the Korean Government (Grant No. 2019M3A9H1030682) and by the Konkuk University Researcher Fund (2021).