Multidrug-resistance of cancer cells and their recovery by regulating expressions of DAP kinase-related molecules

本研究旨在探讨死亡相关蛋白激酶（Death-associated Protein Kinase， DAPK）抗癌分子靶向治疗的可能性。(1) DAPK敲低可调节癌细胞的抗癌药物敏感性。i)通过转染DAPK特异性siRNA靶向敲低DAPK可增强Fas/ trail介导的人子宫内膜腺癌细胞的凋亡易感性。这些结果表明，DAP激酶可能是人类子宫内膜癌患者抗癌分子靶向治疗的有力候选药物。ii)靶向敲低DAPK诱导人子宫癌肉瘤细胞和人子宫平滑肌肉瘤细胞凋亡。结果提示，除了子宫内膜腺癌患者外，DAP激酶可作为抗癌分子靶向治疗子宫癌肉瘤和肉瘤患者的候选药物。iii)靶向敲低DAPK可增强人子宫内膜腺癌细胞的5fu敏感性，但不增强vp16敏感性，部分增强cddp敏感性。然而，它并没有提高他们对5fu耐药细胞的5fu敏感性。这些结果表明，DAPK分子靶向治疗可应用于限制性抗癌化疗。(2)通过去甲基化调控DAPK的表达可改善抗癌耐药宫颈癌细胞的部分抗癌药物敏感性。

This study was performed to investigate a possibility of anticancer molecular targeting therapy of Death-associated Protein Kinase (DAPK).(1) DAPK knockdown regulated anticancer drug-sensitivities of cancer cells. i) Targeted DAPK knockdown by DAPK-specific siRNA transfections enhanced the Fas/TRAIL-mediated apoptotic susceptibility in human endometrial adenocarcinoma cells. These results indicate that DAP kinase can be a powerful candidate of anticancer molecularly targeting therapy for human endometrial cancer patients. ii) Targeted DAPK knockdown induced apoptosis in human uterine carcinosarcoma cells and human uterine leiomyosarcoma cells. The results suggest that DAP kinase can be a candidate of anticancer molecularly targeting therapy for uterine carcinosarcoma and sarcoma patients in addition to endometrial adenocarcinoma patients. iii) Targeted DAPK knockdown enhanced 5FU-sensitivity but not VP16-sensitivity, and enhanced partially CDDP-sensitivity in human endometrial adenocarcinoma cells. However, it did not improve their 5FU-sensitivities in the 5FU-resistant cells. These results indicate that the molecular targeting therapy of DAPK can be applied to restricted anticancer chemotherapies.(2) Regulation of DAPK expression by demethylation improved some of anticancer drug-sensitivities in anticancer drug-resistant cervical cancer cells.