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

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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).

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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