The small chemical enzyme inhibitor 5-phenylnicotinic acid/CD13 inhibits cell migration and invasion of tartrate-resistant acid phosphatase/ACP5-overexpressing MDA-MB-231 breast cancer cells.

Abstract

Tartrate-resistant acid phosphatase (TRAP/ACP5/uteroferrin/purple acid phosphatase/PP5) has received considerable attention as a newly discovered proinvasion metastasis driver associated with different malignancies. This renders TRAP an interesting target for novel anti-cancer therapy approaches. TRAP exists as two isoforms, 5a and 5b, where the 5a isoform represents an enzymatically less active monomeric precursor to the more enzymatically active 5b isoform generated by proteolytic excision of a repressive loop domain. Recently, three novel lead compounds were identified by fragment-based screening and demonstrated to be efficient TRAP enzyme inhibitors in vitro. We conclude that one of the three compounds i.e. 5-phenylnicotinic acid (CD13) was efficient as a TRAP inhibitor with Kic values in the low micromolar range towards the TRAP 5b isoform, but was not able to inhibit the TRAP 5a isoform. Structure-based docking revealed similar interactions of CD13 with the active site in both TRAP isoforms. In stably TRAP-overexpressing MDA-MB-231 breast cancer cells, CD13 inhibited intracellular TRAP activity and showed no cytotoxicity at 200 µM. Furthermore, CD13 selectively blocked the TRAP 5b isoform compared to the TRAP 5a in cultured cells, indicating the usefulness of CD13 for assessing the different biological functions of the two TRAP isoforms 5a and 5b in cell systems. Moreover, inhibition of cell migration and invasion of stably TRAP-overexpressing MDA-MB-231 by CD13 was observed. These data establish a proof of principle that a small chemical inhibitor of the TRAP enzyme can block TRAP-dependent functions in cancer cells.

• Authors: Michael Krumpel, Anja Reithmeier, Teresa Senge, Toni Andreas Baeumler, Martin Frank, Per-Georg Nyholm, Barbro Ek-Rylander, Göran Andersson
• Journal: Experimental cell research (Exp Cell Res) Vol. 339 Issue 1 Pg. 154-62 (Nov 15 2015) ISSN: 1090-2422 [Electronic] United States
• PMID: 26428664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Hydroxybenzoates
• Isoenzymes
• Nicotinic Acids
• RNA, Messenger
• ACP5 protein, human
• Acid Phosphatase
• Tartrate-Resistant Acid Phosphatase
• CD13 Antigens
• phenolic acid

Topics

• Acid Phosphatase (genetics, metabolism)
• Blotting, Western
• Breast Neoplasms (drug therapy, metabolism, pathology)
• CD13 Antigens (genetics, metabolism)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Hydroxybenzoates (chemistry)
• Isoenzymes (genetics, metabolism)
• Nicotinic Acids (pharmacology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tartrate-Resistant Acid Phosphatase
• Tumor Cells, Cultured