研究発表を行った学会；AACR: American Association for Cancer Research, 95th Annual Meeting, March 27-31, 2004, Orlando, Florida, US
タイトル；Enhanced Sensitivity of Tumor Cells to Chemotherapeutic Agents by Activation of FUS1 Tumor Suppressor Gene in Lung Cancer Cells
発表者；佐々木　治一郎　氏
　　　（熊本大学　医学部附属病院　呼吸器内科）
Abstract；
FUS1 is a novel tumor suppressor gene (TSG) identified in the human chromosome 3p21.3 region that is deleted in many cancers. We previously found that FUS1 TSG was inactivated in many primary lung cancers and cancer-derived cell lines by either the loss of expression or the deficiency of the posttranslational myristoylation modification of the wild-type (wt)-Fus1 proteins. We also demonstrated that exogenous expression of the wt-FUS1 by plasmid- or adenoviral vector-mediated gene transfer significantly inhibited tumor cell growth, induced apoptosis, and altered cell cycle kinetics in 3p21.3-deficient lung cancer cells in vitro and efficiently suppressed tumor growth and inhibited tumor progression and metastases in human lung cancer xenograft mouse models. Based on these pre-clinical investigations, a phase I clinical trial is now undertaking in advanced non-small cell lung cancer patients using systemic administration of DOTAP-cholesterol-complexed wt-FUS1-expressing plasmid DNA (FUS1-lipoplex). In this study, we explored the capability of the wt-FUS1 gene product as a modulator of chemotherapeutic drugs for enhancing chemotherapeutic potency and overcoming drug resistance in lung cancer cells. We found that a transient expression of the wt-Fus1 protein in FUS1-expressing plasmid-transfected H1299 cells significantly enhanced the cisplatin-mediated inhibitory effect on tumor cell growth at a low-dose (1 micro molar) of cisplatin treatment. In addition, a stable expression of the wt-FUS1 gene, which is under the control of a ponasterone A-inducible promoter, reduced more than 30% of IC50 values of both cisplatin and paclitaxel treatments in H1299 cells, even at a low level of induced Fus1 expression. However, the maximum stable expression of a functionally deficient mutant Fus1 protein (mt-Fus1) in a similar inducible system did not enhance the sensitivity of tumor cells to these drugs. Furthermore, a significant increase in apoptotic cell populations were detected in cells with the induced expression of the wt-Fus1 protein but not in those with induced expression of mt-Fus1, as shown by a FACS analysis with TUNEL reaction. These results suggest that the wt-Fus1 may play a critical role in modulating the sensitivity of tumor cells to the chemotherapeutic agents, especially, to DNA damaging agents such as cisplatin and that a combination treatment with the FUS1-lipoplex-mediated molecular therapy and the cisplatin or taxcel-based chemotherapy may be an efficient treatment strategy for lung cancer.