Department of Hematology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, 200080, People's Republic of China.
Int J Hematol. 2014 Jan;99(1):57-68. doi: 10.1007/s12185-013-1484-8. Epub 2013 Dec 5.
Previous studies have demonstrated that activator of G-protein signaling 3 (AGS3; also known as GPSM1), a member of the AGS family, plays an important anti-apoptotic role through enhancing the phosphorylation of cyclic AMP response element-binding protein (p-CREB). In this report, we delineate the anti-apoptotic role of AGS3 in multiple myeloma (MM). To do this, we developed a cell apoptotic model induced by doxorubicin in MM. Our data indicate that decreased expression of AGS3 is correlated with reduced levels of p-CREB in the apoptotic model. The negative role of AGS3 in cell apoptosis was further confirmed by knocking down AGS3. The microenvironment has been shown to influence tumor cell phenotype in response to chemotherapy. Since cell adhesion-mediated drug resistance remains a major obstacle for successful treatment of MM, we constructed a cell adhesion model in MM and detected the changing of AGS3 protein expression. AGS3 siRNA reversed the high rate of MM cell adhesion to either fibronectin or HS-5 cells. Consistent with the reduced adhesion rate, the cells also exhibited reduced drug resistance to doxorubicin, mitoxantrone, and dexamethasone. Collectively, these data indicate that AGS3 may be represented as a good candidate for pursuing clinical trials in MM. Moreover, our data provide a clinical therapeutic target for MM and potentially other tumors that home and/or metastasize to the bone.
先前的研究表明，G 蛋白信号转导激活因子 3（AGS3；也称为 GPSM1）作为 AGS 家族的一员，通过增强环磷酸腺苷反应元件结合蛋白（p-CREB）的磷酸化，发挥重要的抗凋亡作用。在本报告中，我们阐述了 AGS3 在多发性骨髓瘤（MM）中的抗凋亡作用。为此，我们建立了 MM 细胞中阿霉素诱导的细胞凋亡模型。我们的数据表明，AGS3 表达下调与凋亡模型中 p-CREB 水平降低相关。AGS3 敲低进一步证实了 AGS3 在细胞凋亡中的负调控作用。微环境已被证明会影响肿瘤细胞对化疗的表型。由于细胞黏附介导的耐药性仍然是成功治疗 MM 的主要障碍，我们在 MM 中构建了细胞黏附模型，并检测了 AGS3 蛋白表达的变化。AGS3 siRNA 逆转了 MM 细胞对纤连蛋白或 HS-5 细胞的高黏附率。与黏附率降低一致，细胞对阿霉素、米托蒽醌和地塞米松的耐药性也降低。总之，这些数据表明 AGS3 可能是 MM 临床研究的良好候选者。此外，我们的数据为 MM 及潜在的其他归巢和/或转移至骨骼的肿瘤提供了临床治疗靶点。
