High-throughput Solid-Phase Kinome Transfection Platforms Identify Chemoresistant Genes in Human Cancers: Role of TAOK3 in Breast Cancer Taxol Resistance

• Main Authors: Tsung-Ching Lai, 賴宗慶
• Other Authors: Michael Hsiao
• Format: Others
• Language: en_US
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/9uw98s

博士 === 國立陽明大學 === 微生物及免疫學研究所 === 105 === Protein kinase signaling regulations play many key roles in variant cancer malignancies, like survival, proliferation or metastasis. There were many kinase inhibitors that were designed and produced for cancer therapy in clinical practice. The development of effective chemotherapy resistance is considered to be one of the most challenging issues for clinicians and scientists. In this study, a lentiviral shRNA-based high-throughput screening platform was designed and developed to screen global kinome in order to find new therapeutic targets in paclitaxel-resistant breast cancer cells. A less-studied kinase gene, TAOK3, was identified from 724 kinase genes screened. TAOK3 shRNA exhibited the most significant reduction of IC50 values in response to paclitaxel treatment. Furthermore, ectopic overexpression of TAOK3 resulted in paclitaxel resistance breast cancer cells sensitive to paclitaxel treatment in vitro and in vivo. Global microarray and phosphoprotein array analyses were performed to determine TAOK3 downstream pathways and genes that induced paclitaxel resistance. Our results showed TAOK3 overexpression increased paclitaxel resistance through upregulating the phosphorylation of p38 mitogen-activated protein kinase, MAPK14, and RELA. Treatment of p38 inhibitor and NF-kB inhibitor in TAOK3 overexpressed cells induced chemosensitization effects of the paclitaxel-resistant breast cancer cells. Interestingly, the expression of TOAK3 also corresponded to the paclitaxel resistance status in lung cancer cell lines. In clinical cohorts, TAOK3 protein expressions also have a significant association to recurrence, and poor patient survival in both breast and lung cancer. In summary, the results showed that TAOK3 overexpression induced paclitaxel resistance through modulation p38 and NF-B phosphorylation in both breast and lung cancer cells. TAOK3 may be a feasible target to develop inhibitor to treat breast and lung cancer patients resistant to paclitaxel treatment.