Itraconazole inhibits endothelial cell migration by disrupting inositol 2 pyrophosphate-dependent focal adhesion dynamics and cytoskeletal remodeling

Journal article

The antifungal drug itraconazole has been repurposed to anti-angiogenic agent, but the mechanisms of action have been elusive. Here we report that itraconazole disrupts focal adhesion dynamics and cytoskeletal remodeling, which requires 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7). We find that inositol hexakisphosphate kinase 1 (IP6K1) binds Arp2 and generates 5-InsP7 to recruit coronin, a negative regulator of the Arp2/3 complex. IP6K1 also produces focal adhesion-enriched 5-InsP7, which binds focal adhesion kinase (FAK) at the FERM domain to promote its dimerization and phosphorylation. Itraconazole treatment elicits displacement of IP6K1/5-InsP7, thus augments 5-InsP7-mediated inhibition of Arp2/3 complex and reduces 5-InsP7-mediated FAK dimerization. Itraconazole-treated cells display reduced focal adhesion dynamics and actin cytoskeleton remodeling. Accordingly, itraconazole severely disrupts cell motility, an essential component of angiogenesis. These results demonstrate critical roles of IP6K1-generated 5-InsP7 in regulating focal adhesion dynamics and actin cytoskeleton remodeling and reveal functional mechanisms by which itraconazole inhibits cell motility.

Authors: Qi, J; Cheng, W; Gao, Z; Shipton, ML; Riley, AM

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Biomedicine and Pharmacotherapy
• Volume: 161
• Article number: 114449
• Publication date: 2023-02-27
• Acceptance date: 2023-02-23
• DOI: 10.1016/j.biopha.2023.114449
• ISSN: 0753-3322
• Language: English
• Keywords: FFR