Calpain-Mediated Integrin Deregulation as a Novel Mode of Action for the Anticancer Gallium Compound KP46
| Autor: | Rosa Lemmens-Gruber, Gernot Walko, Bernhard K. Keppler, Thomas Schöfl, Christian R. Kowol, Martin Holcmann, Nastasia Wilfinger, Walter Berger, Johannes Gojo, Ute Jungwirth, Theresa Tuder, Petra Heffeter, Sushilla van Schoonhoven, Karin Nowikovsky |
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| Rok vydání: | 2014 |
| Předmět: |
Integrins
Cancer Research Cell Integrin Mice SCID Collagen receptor Focal adhesion Mice Random Allocation Cell Line Tumor Neoplasms Cell Adhesion Organometallic Compounds medicine Animals Humans Cell adhesion Mice Inbred BALB C biology Calpain Chemistry Cell adhesion molecule Oxyquinoline Xenograft Model Antitumor Assays Cell biology medicine.anatomical_structure Oncology Biochemistry Apoptosis biology.protein Female Caco-2 Cells |
| Zdroj: | Molecular Cancer Therapeutics. 13:2436-2449 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-14-0087 |
| Popis: | On the basis of enhanced tumor accumulation and bone affinity, gallium compounds are under development as anticancer and antimetastatic agents. In this study, we analyzed molecular targets of one of the lead anticancer gallium complexes [KP46, Tris(8-quinolinolato)gallium(III)] focusing on colon and lung cancer. Within a few hours, KP46 treatment at low micromolar concentrations induced cell body contraction and loss of adhesion followed by prompt cell decomposition. This rapid KP46-induced cell death lacked classic apoptotic features and was insensitive toward a pan–caspase inhibitor. Surprisingly, however, it was accompanied by upregulation of proapoptotic Bcl-2 family members. Furthermore, a Bax- but not a p53-knockout HCT-116 subline exhibited significant KP46 resistance. Rapid KP46-induced detachment was accompanied by downregulation of focal adhesion proteins, including several integrin subunits. Loss of integrin-β1 and talin plasma membrane localization corresponded to reduced binding of RGD (Arg–Gly–Asp) peptides to KP46-treated cells. Accordingly, KP46-induced cell death and destabilization of integrins were enhanced by culture on collagen type I, a major integrin ligand. In contrast, KP46-mediated adhesion defects were partially rescued by Mg2+ ions, promoting integrin-mediated cell adhesion. Focal adhesion dynamics are regulated by calpains via cleavage of multiple cell adhesion molecules. Cotreatment with the cell-permeable calpain inhibitor PD150606 diminished KP46-mediated integrin destabilization and rapid cell death induction. KP46 treatment distinctly inhibited HCT-116 colon cancer xenograft in vivo by causing reduced integrin plasma membrane localization, tissue disintegration, and intense tumor necrosis. This study identifies integrin deregulation via a calpain-mediated mechanism as a novel mode of action for the anticancer gallium compound KP46. Mol Cancer Ther; 13(10); 2436–49. ©2014 AACR. |
| Databáze: | OpenAIRE |
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