Involvement of actin cytoskeletal modifications in the inhibition of triple-negative breast cancer growth and metastasis by nimbolide

Abstract

Triple-negative breast cancers (TNBCs) are aggressive cancers, which currently do not have effective treatment options. Migration and establishment of metastatic colonies require dynamic cytoskeletal modifications characterized by polymerization and depolymerization of actin. Studies have demonstrated a direct molecular link between the integrin-focal adhesion kinase (FAK) pathway and cytoskeletal modifications. Nimbolide, a major bioactive compound present in neem leaves, shows promising anti-cancer effect on various cancers. In this study, we have demonstrated the growth and metastasis inhibitory potential of nimbolide on TNBC cells. Nimbolide inhibited cell proliferation, migratory, and invasive abilities of TNBC cells and also changed the shape of MDA-MB-231 cells, which is correlated with cytoskeletal changes including actin depolymerization. Furthermore, analysis revealed that integrins αV and β3, ILK, FAK, and PAK levels were downregulated by nimbolide. Even in cells where Rac1/Cdc42 was constitutively activated, nimbolide inhibited the formation of filopodial structures. Immunofluorescence analysis of phosphorylated p21 activated kinase (pPAK) showed reduced expression in nimbolide-treated cells. Nimbolide significantly reduced the metastatic colony formation in lung, liver, and brain of athymic nude mice. In conclusion, our data demonstrate that nimbolide inhibits TNBC by altering the integrin and FAK signaling pathway.

Keywords

• nimbolide
• triple-negative breast cancer
• metastasis
• integrin-FAK
• Rac1/Cdc42
• actin depolymerization