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 embryonal 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.
Keywords: Hsp90, 17AAG, extracellular matrix, integrins, actin-cytoskeleton, Pharmacological inhibition, tumor cells, integrin signaling, neuroblastoma, integrin-cytoskeleton, cell adhesion, mRNA
Medicinal Chemistry
Title: Pharmacological Inhibition of Hsp90 as a Novel Antitumor Strategy to Target Cytoarchitecture Through Extracellular Matrix Signaling
Volume: 7 Issue: 5
Author(s): Vishal Chaturvedi, Jonnala Ujwal Kumar, Khande Rao Paithankar, Perumal Vanathi and Amere Subbarao Sreedhar
Affiliation:
Keywords: Hsp90, 17AAG, extracellular matrix, integrins, actin-cytoskeleton, Pharmacological inhibition, tumor cells, integrin signaling, neuroblastoma, integrin-cytoskeleton, cell adhesion, mRNA
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 embryonal 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.
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Chaturvedi Vishal, Ujwal Kumar Jonnala, Rao Paithankar Khande, Vanathi Perumal and Subbarao Sreedhar Amere, Pharmacological Inhibition of Hsp90 as a Novel Antitumor Strategy to Target Cytoarchitecture Through Extracellular Matrix Signaling, Medicinal Chemistry 2011; 7 (5) . https://dx.doi.org/10.2174/157340611796799212
DOI https://dx.doi.org/10.2174/157340611796799212 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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