LKB1 is crucial for TRAIL-mediated apoptosis induction in osteosarcoma.
LKB1 is crucial for TRAIL-mediated apoptosis induction in osteosarcoma.
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发表时间：
2007-03
影响因子：
2
通讯作者：
Shintaro Takeda;A. Iwai;M. Nakashima;D. Fujikura;S. Chiba;Hong Mei Li;J. Uehara;S. Kawaguchi;M. Kaya;S. Nagoya;T. Wada;Junying Yuan;S. Rayter;A. Ashworth;J. Reed;T. Yamashita;T. Uede;T. Miyazaki
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作者：
Shintaro Takeda;A. Iwai;M. Nakashima;D. Fujikura;S. Chiba;Hong Mei Li;J. Uehara;S. Kawaguchi;M. Kaya;S. Nagoya;T. Wada;Junying Yuan;S. Rayter;A. Ashworth;J. Reed;T. Yamashita;T. Uede;T. Miyazaki
背景尽管骨肉瘤的化疗和手术治疗取得了进展，但仍难以取得满意的结果。需要开发新的治疗方式来改善这些治疗。肿瘤坏死因子相关凋亡诱导配体（TNF-related apoptosis inducing ligand，TRAIL）是一种选择性的凋亡诱导剂，在大多数肿瘤细胞中是如此，而在正常细胞中则不然。因此，TRAIL是治疗肿瘤的良好候选靶点。然而，骨肉瘤细胞对TRAIL诱导的凋亡的敏感性低于其他类型的肿瘤细胞。最近，死亡相关蛋白3（DAP 3）被证明通过激活caspase-8在TRAIL介导的细胞凋亡中起关键作用。在这里，我们发现LKB 1，丝氨酸/苏氨酸激酶，在骨和软组织肉瘤细胞中表达，与DAP 3相关。我们还证明了DAP 3的表达诱导骨肉瘤细胞凋亡。此外，LKB 1的表达诱导骨肉瘤细胞凋亡，LKB 1与DAP 3的共表达强烈诱导骨肉瘤细胞凋亡。此外，LKB 1激酶死亡突变体LKB 1（K78 M）的表达抑制了DAP 3诱导的细胞凋亡。这些结果表明，LKB 1是关键的TRAIL诱导的凋亡诱导，协同DAP 3在骨肉瘤细胞。LKB 1和DAP 3可能是治疗骨肉瘤的关键靶分子。
BACKGROUND Despite improvements in chemotherapy and surgery in the treatment of osteosarcoma, satisfactory results are still difficult to achieve. New therapeutic modalities need to be developed for the improvement of these treatments. TRAIL (TNF-related apoptosis inducing ligand) is known as a selective apoptosis inducer in most tumor cells, but not in normal cells. Therefore, TRAIL is a good candidate target for the treatment of tumors. However, sensitivity of osteosarcoma cells to TRAIL-induced apoptosis is lower than that of other types of tumor cells. Recently, DAP3 (death associated protein 3) was demonstrated to play a critical role in TRAIL-mediated apoptosis through activation of pro-caspase-8. Here, we found that LKB1, a serine/threonine kinase, expressed in bone and soft tissue sarcoma cells, associated with DAP3. We also demonstrated that expression of DAP3 induced apoptosis in osteosarcoma cells. Furthermore, expression of LKB1 induced apoptosis and co-expression of LKB1 with DAP3 strongly induced apoptosis in osteosarcoma cells. In addition, expression of LKB1 kinase dead mutant, LKB1 (K78M), inhibited DAP3-induced apoptosis in these cells. These results suggest that LKB1 is critical for TRAIL-induced apoptosis induction, cooperating with DAP3 in osteosarcoma cells. It is predicted that LKB1 and DAP3 could be critical target molecules for the treatment of osteosarcomas.