HtrA4 Protease Promotes Chemotherapeutic-Dependent Cancer Cell Death

The HtrA4 human protease is crucial in placentation and embryo implantation, and its altered level is connected with pre-eclampsia. The meta-analyses of microarray assays revealed that the HtrA4 level is changed in brain tumors and breast and prostate cancers, which suggests its involvement in oncogenesis. In spite of the HtrA4 involvement in important physiological and pathological processes, its function in the cell is poorly understood. In this work, using lung and breast cancer cell lines, we showed for the first time that the full-length HtrA4 and its N-terminally deleted variant promote cancer cell death induced by chemotherapeutic drugs by enhancing apoptosis. The effect is dependent on the HtrA4 proteolytic activity, and the N-terminally deleted HtrA4 is more efficient in the cell death stimulation. Furthermore, HtrA4 increases the effect of chemotherapeutics on the clonogenic potential and motility of cancer cells, and it increases cell cycle arrest at the G2/M phase. HtrA4 may modulate cell death by degrading the anti-apoptotic XIAP protein and also by proteolysis of the executioner pro-caspase 7 and cytoskeletal proteins, actin and β-tubulin. These findings provide new insight into the mechanism of the HtrA4 protease function in cell death and oncogenesis, and they may help to develop new anti-cancer therapeutic strategies.