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Review
. 2017 Oct 4;5(4):59.
doi: 10.3390/biomedicines5040059.

Restoration of DAP Kinase Tumor Suppressor Function: A Therapeutic Strategy to Selectively Induce Apoptosis in Cancer Cells Using Immunokinase Fusion Proteins

Mehmet Kemal Tur  1 , Adebukola K Daramola  2 , Stefan Gattenlöhner  3 , Marco Herling  4   5 , Shivan Chetty  6 , Stefan Barth  7
Affiliations
Review

Restoration of DAP Kinase Tumor Suppressor Function: A Therapeutic Strategy to Selectively Induce Apoptosis in Cancer Cells Using Immunokinase Fusion Proteins

Mehmet Kemal Tur et al. Biomedicines. .

Abstract

Targeted cancer immunotherapy is designed to selectively eliminate tumor cells without harming the surrounding healthy tissues. The death-associated protein kinases (DAPk) are a family of proapoptotic proteins that play a vital role in the regulation of cellular process and have been identified as positive mediators of apoptosis via extrinsic and intrinsic death-regulating signaling pathways. Tumor suppressor activities have been shown for DAPk1 and DAPk2 and they are downregulated in e.g., Hodgkin's (HL) and B cell lymphoma (CLL), respectively. Here, we review a targeted therapeutic approach which involves reconstitution of DAPks by the generation of immunokinase fusion proteins. These recombinant proteins consist of a disease-specific ligand fused to a modified version of DAPk1 or DAPk2. HL was targeted via CD30 and B-CLL via CD22 cell surface antigens.

Keywords: apoptosis inducers; cancer immunotherapy; death-associated protein kinases (DAPk); humanised cytolytic fusion proteins (hCFPs).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the multi-domain organization of death associated protein kinase DAPk1 (death-associated protein kinases 1), and ZIPk. The catalytic domain, a death domain, and ankyrin repeats, which may mediate its interaction with other proteins. The cytoskeleton-binding region is responsible for DAPk1 intracellular localization to actin microfilaments. DAPk1 and DAPk2 are activated by a rise in cytosolic calcium concentrations resulting from cellular stresses, through binding of calcium-activated calmodulin [33]. NLS = nuclear localization signal.
Figure 2
Figure 2
Activation of different DAPk signaling cascade by different stimuli. Based on the signal input and cell context, the DAPk family of genes play a crucial role is deciding the outcome of whether a cell survives or undergoes apoptosis. Activated DAPk proteins may initiate p53-dependent or independent apoptosis or mediate an autophagic programmed cell death [39].
Figure 3
Figure 3
Percentages of DAPk gene methylation in different tumors. Minimal and maximal percentage of DAPk methylation is represented in dark blue and light blue, respectively, as identified by different studies [64,65,66,67,68,69,70,71,72,73,74]. RCC: renal cell cancer, CXCA: cervical cancer.
Figure 4
Figure 4
Schematic representation of an expression cassette for a recombinant immunokinase fusion protein. Under the expression of a strong CMV promoter, the N-terminal Igkappa leader sequence allows direction of expressed protein into the media of the expressing cell line. A C-terminal His6 tag sequence allows for affinity purification of the recombinant protein via an IMAC purification system.
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