Down-regulation of cathepsin S and matrix metalloproteinase-9 via Src, a non-receptor tyrosine kinase, suppresses triple-negative breast cancer growth and metastasis.

Abstract

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer with poor prognosis. In the present study, we demonstrated that Src, a non-receptor tyrosine kinase, might provide an effective therapeutic strategy to overcome TNBC invasion and metastasis, which are mediated via the synergistic action of the lysosomal enzyme cathepsin S (CTSS) and gelatinase MMP-9. Knock-down of MMP-9 and CTSS using siRNAs resulted in a synergistic suppression of MDA-MB-231 cell invasion, which was similarly observed with pharmacological inhibitors. During the screening of new drug candidates that suppress both CTSS and MMP-9, BJ-2302, a novel 7-azaindolin-2-one derivative, was discovered. Src, an upstream activator of both pathways (PI3K/Akt and Ras/Raf/ERK) responsible for the expression of CTSS and MMP-9, was identified as a high-affinity target of BJ-2302 (IC90: 3.23 µM) through a Src kinase assay and a drug affinity responsive target stability (DARTS) assay. BJ-2302 effectively suppressed MDA-MB-231 cell invasion (Matrigel invasion assay) and metastasis (chorioallantoic membrane assay xenografted with MDA-MB-231-luc2-tdTomato cancer cells). Unlike Z-FL-COCHO (potent CTSS inhibitor), BJ-2302 did not induce any cytotoxicity in MCF-10A normal breast epithelial cells. Additionally, BJ-2302 (1 mg/kg) strongly suppressed TNBC cell proliferation in vitro and tumor growth in a xenograft mouse tumor model. The anti-metastatic and anti-tumor effects of BJ-2302 were superior to those of Z-FL-COCHO (1 mg/kg) or batimastat (30 mg/kg), a pan-MMP inhibitor. In summary, inhibition of Src kinase suppressed TNBC tumor growth and metastasis, and Src inhibitors such as BJ-2302 may constitute a novel therapeutic tool to treat breast cancer that expresses high levels of CTSS and MMP-9.

• Authors: Jaya Gautam, Suhrid Banskota, Hyunji Lee, Yu-Jeong Lee, Yong Hyun Jeon, Jung-Ae Kim, Byeong-Seon Jeong
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 50 Issue 9 Pg. 1-14 (09 05 2018) ISSN: 2092-6413 [Electronic] United States
• PMID: 30185799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• src-Family Kinases
• Cathepsins
• cathepsin S
• Matrix Metalloproteinase 9

Topics

• Aminopyridines (pharmacology)
• Animals
• Cathepsins (metabolism)
• Cell Proliferation
• Cell Survival
• Chickens
• Chorioallantoic Membrane (metabolism)
• Down-Regulation (drug effects)
• Female
• Humans
• MCF-7 Cells
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Signal Transduction (drug effects)
• Triple Negative Breast Neoplasms (enzymology, pathology)
• Xenograft Model Antitumor Assays
• src-Family Kinases (metabolism)