Calpain-mediated integrin deregulation as a novel mode of action for the anticancer gallium compound KP46
Ute Jungwirth1, Johannes Gojo1, Theresa Tuder1
1Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Abstract:
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 Mg(2+) 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.
Insights
The anticancer gallium compound KP46 induces rapid cancer cell death by disrupting cell adhesion proteins, a novel mechanism involving calpains and integrins, showing efficacy in colon cancer models.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Gallium compounds show promise as anticancer and antimetastatic agents due to tumor accumulation and bone affinity.
- The specific gallium complex Tris(8-quinolinolato)gallium(III) (KP46) is a lead candidate for cancer therapy.
Purpose of the Study:
- To investigate the molecular targets and mechanism of action of the anticancer gallium complex KP46 in colon and lung cancer.
- To elucidate the role of cell adhesion and specific signaling pathways in KP46-induced cancer cell death.
Main Methods:
- Treatment of colon and lung cancer cells with KP46 at low micromolar concentrations.
- Analysis of cell death morphology, caspase activity, and expression of Bcl-2 family members.
- Assessment of KP46 effects in Bax- and p53-knockout HCT-116 cell lines.
- Evaluation of focal adhesion proteins, integrin localization, and RGD peptide binding.
- In vivo studies using HCT-116 colon cancer xenografts.
- Investigation of calpain activity using the inhibitor PD150606.
Main Results:
- KP46 induced rapid cell body contraction, loss of adhesion, and cell decomposition, independent of classic apoptosis.
- Upregulation of proapoptotic Bcl-2 family members and resistance in Bax-knockout cells were observed.
- KP46 treatment led to downregulation of focal adhesion proteins, including integrin-β1 and talin, reducing RGD peptide binding.
- Cell death and integrin destabilization were enhanced by collagen type I and partially rescued by Mg(2+) ions.
- Calpain inhibition diminished KP46-mediated integrin destabilization and cell death.
- In vivo, KP46 inhibited xenograft growth, causing reduced integrin localization, tissue disintegration, and tumor necrosis.
Conclusions:
- KP46 exhibits a novel anticancer mechanism involving rapid cell death through integrin deregulation via a calpain-mediated pathway.
- This mechanism differs from classical apoptosis and highlights the importance of cell adhesion in KP46's antimetastatic potential.
- KP46 demonstrates significant efficacy in inhibiting colon cancer xenografts, supporting its development as an anticancer agent.
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