IKK inhibition by BMS-345541 suppresses breast tumorigenesis and metastases by targeting GD2+ cancer stem cells.

Abstract

We have identified that the ganglioside GD2 is a marker for breast cancer stem cells (BCSCs), and that targeting the enzyme GD3 synthase (GD3S, which regulates GD2 biosynthesis) reduces breast tumorigenesis. The pathways regulating GD2 expression, and their anomalous functions in BCSC, are unclear. Proteomic analysis of GD2+ and GD2- cells from breast cancer cell lines revealed the activation of NFκB signaling in GD2+ cells. Dose- and time-dependent suppression of NFκB signaling by the small molecule inhibitor BMS-345541 reduced GD2+ cells by > 90%. Likewise, BMS-345541 inhibited BCSC GD3S expression, mammosphere formation, and cell migration/invasion in vitro. Breast tumor-bearing mice treated with BMS-345541 showed a statistically significant decrease in tumor volume and exhibited prolonged survival compared to control mice, with a median survival of 78 d for the BMS-345541-treated group vs. 58 d for the controls. Moreover, in an experimental metastases model, treatment with BMS-345541 reduced the lung metastases by > 5-fold. These data suggest that GD2 expression and function,and NFκB signaling, are related, and they control BCSCs tumorigenic characteristics. Thus, the suppression of NFκB signaling by BMS-345541 is a potentially important advance in controlling breast cancer growth and metastases.

• Authors: Venkata Lokesh Battula, Khoa Nguyen, Jeff Sun, Mary Kathryn Pitner, Bin Yuan, Chandra Bartholomeusz, Numsen Hail, Michael Andreeff
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 23 Pg. 36936-36949 (Jun 06 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28415808 (Publication Type: Journal Article)

Chemical References

• 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
• Gangliosides
• Imidazoles
• Quinoxalines
• ganglioside, GD2
• Sialyltransferases
• alpha-N-acetylneuraminate alpha-2,8-sialyltransferase
• I-kappa B Kinase

Topics

• Animals
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Carcinogenesis (drug effects, genetics, metabolism)
• Cell Line, Tumor
• Gangliosides (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• I-kappa B Kinase (antagonists & inhibitors, genetics, metabolism)
• Imidazoles (pharmacology)
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Neoplasm Metastasis
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Quinoxalines (pharmacology)
• RNA Interference
• Sialyltransferases (genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• Xenograft Model Antitumor Assays