Itraconazole inhibits endothelial cell migration by disrupting inositol pyrophosphate-dependent focal adhesion dynamics and cytoskeletal remodeling.
| Publication Type | Academic Article |
| Authors | Qi J, Cheng W, Gao Z, Chen Y, Shipton M, Furkert D, Chin A, Riley A, Fiedler D, Potter B, Fu C |
| Journal | Biomed Pharmacother |
| Volume | 161 |
| Pagination | 114449 |
| Date Published | 02/27/2023 |
| ISSN | 1950-6007 |
| Keywords | Itraconazole, Inositol Phosphates |
| Abstract | 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. |
| DOI | 10.1016/j.biopha.2023.114449 |
| PubMed ID | 36857911 |
| PubMed Central ID | PMC7614367 |