HSP90 modulates actin dynamics: inhibition of HSP90 leads to decreased cell motility and impairs invasion.
HSP90, a major molecular chaperone, plays an essential role in the maintenance of several signaling molecules. Inhibition of HSP90 by inhibitors such as 17-allylamino-demethoxy-geldanamycin (17AAG) is known to induce apoptosis in various cancer cells by decreasing the activation or expression of pro-survival molecules such as protein kinase B (Akt). While we did not observe either decrease in expression or activation of pro-survival signaling molecules in human breast cancer cells upon inhibiting HSP90 with 17AAG, we did observe a decrease in cell motility of transformed cells, and cell motility and invasion of cancer cells. We found a significant decrease in the number of filopodia and lamellipodia, and in the F-actin bundles upon HSP90 inhibition. Our results show no change in the active forms or total levels of FAK and Pax, or in the activation of Rac-1 and Cdc-42; however increased levels of HSP90, HSP90α and HSP70 were observed upon HSP90 inhibition. Co-immuno-precipitation of HSP90 reveals interaction of HSP90 with G-actin, which increases upon HSP90 inhibition. FRET results show a significant decrease in interaction between actin monomers, leading to decreased actin polymerization upon HSP90 inhibition. We observed a decrease in the invasion of human breast cancer cells in the matrigel assay upon HSP90 inhibition. Over-expression of αB-crystallin, known to be involved in actin dynamics, did not abrogate the effect of HSP90 inhibition. Our work provides the molecular mechanism by which HSP90 inhibition delays cell migration and should be useful in developing cancer treatment strategies with known anti-cancer drugs such as cisplatin in combination with HSP90 inhibitors.
Taiyab
Aftab
A
Centre for Cellular and Molecular Biology, Council for Scientific and Industrial Research, Hyderabad, India.
Rao
Ch Mohan
ChM
D000199:Actins / Q000378:metabolism*; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D005260:Female; D005455:Fluorescent Antibody Technique; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D007797:Laminin / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D015398:Signal Transduction; D014945:Wound Healing
D000199:Actins; D016227:Benzoquinones; D004338:Drug Combinations; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; C112765:tanespimycin; D003094:Collagen