title: Pharmacological inhibition of Hsp90 as a novel antitumor strategy to target cytoarchitecture through extracellular matrix signaling.
abstract: Pharmacological inhibition of Hsp90 in tumor cells induces anticancer effects through the destabilization of several oncogenic signaling molecules. Although there were reports that Hsp90 inhibition compromises cellular integrity, how this affects the cell adhesion through extracellular matrix (ECM) and integrin signaling is not known. Using human neuroblastoma (IMR-32), cervical (HeLa) and breast (MCF-7) cancer cells, and mouse embryonic carcinoma (PCC-4) cells, and using different substratum, glass, plastic, fibronectin, and matrigel, we demonstrate 17AAG induced alterations in integrin cross-linking with the actin cytoskeleton. The 17AAG treatment of cells resulted in decreased mRNA levels and confined surface expression of three major beta1 family of integrins namely α2, α3, and α5 in IMR-32, HeLa and PCC-4 cells, but showed induced mRNA levels and surface expression in MCF-7 cells. Loss of surface expression of integrins correlated with inhibition of focal adhesion kinase (FAK) and mitogen regulated kinase (ERK1/2) activities, in contrast, induced integrin expression in MCF-7 correlated with activation of these kinases. Prolonged treatment but not the pretreatment (2 h) with 17AAG resulted in destabilized actin cytoskeleton, delayed wound repair, and limited colony forming ability of tumor cells on soft agar. Conclusively, we show that Hsp90 inhibition targets cell adhesion, which may relate to the inhibition of integrin signaling and inhibition of integrin-cytoskeleton crosslinking.
authors.affiliation: Centre for Cellular and Molecular Biology, Hyderabad, India.
authors.forename: Vishal
authors.initials: V
authors.lastname: Chaturvedi
authors.forename: Jonnala Ujwal
authors.initials: JU
authors.lastname: Kumar
authors.forename: Khande Rao
authors.initials: KR
authors.lastname: Paithankar
authors.forename: Perumal
authors.initials: P
authors.lastname: Vanathi
authors.forename: Amere Subbarao
authors.initials: AS
authors.lastname: Sreedhar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D016023:Integrins; D012333:RNA, Messenger