Vacuolin-1 inhibits endosomal trafficking and metastasis via CapZβ.

Abstract

Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have previously found that small chemical vacuolin-1 (V1) potently inhibits autophagosome-lysosome fusion and general endosomal-lysosomal degradation. Here, we assessed the anti-metastatic activity of V1 both in vitro and in vivo. V1 significantly inhibits colony formation, migration, and invasion of various cancer cells in vitro. It also compromises the assembly-disassembly dynamics of focal adhesions (FAs) by inhibiting the recycling and degradation of integrins. In various experimental or transgenic mouse models, V1 significantly suppresses the metastasis and/or tumor growth of breast cancer or melanoma. We further identified capping protein Zβ (CapZβ) as a V1 binding protein and showed that it is required for the V1-mediated inhibition of migration and metastasis of cancer cells. Collectively, our results indicate that V1 targets CapZβ to inhibit endosomal trafficking and metastasis.

• Authors: Zuodong Ye, Dawei Wang, Yingying Lu, Yunjiao He, Jingting Yu, Wenjie Wei, Chang Chen, Rui Wang, Liang Zhang, Liangren Zhang, Minh T N Le, William C Cho, Mengsu Yang, Hongmin Zhang, Jianbo Yue
• Journal: Oncogene (Oncogene) Vol. 40 Issue 10 Pg. 1775-1791 (03 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 33564074 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CAPZB protein, human
• CapZ Actin Capping Protein
• Heterocyclic Compounds, 4 or More Rings
• Integrins
• vacuolin-1

Topics

• Animals
• Autophagosomes (drug effects)
• Biological Transport (genetics)
• Breast Neoplasms (drug therapy, genetics, pathology, secondary)
• CapZ Actin Capping Protein (genetics)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Endosomes (drug effects)
• Female
• Focal Adhesions (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Humans
• Integrins (genetics)
• Lysosomes (drug effects)
• Mice
• Mice, Transgenic
• Neoplasm Metastasis (drug therapy, genetics, pathology)
• Protein Binding (drug effects)