Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Clin Cancer Res. 2011 Oct 15;17(20):6500-9. doi: 10.1158/1078-0432.CCR-11-1036. Epub 2011 Aug 19.
The transcription factor specificity protein 1 (Sp1) controls number of cellular processes by regulating the expression of critical cell cycle, differentiation, and apoptosis-related genes containing proximal GC/GT-rich promoter elements. We here provide experimental and clinical evidence that Sp1 plays an important regulatory role in multiple myeloma (MM) cell growth and survival.
We have investigated the functional Sp1 activity in MM cells using a plasmid with Firefly luciferase reporter gene driven by Sp1-responsive promoter. We have also used both siRNA- and short hairpin RNA-mediated Sp1 knockdown to investigate the growth and survival effects of Sp1 on MM cells and further investigated the anti-MM activity of terameprocol (TMP), a small molecule that specifically competes with Sp1-DNA binding in vitro and in vivo.
We have confirmed high Sp1 activity in MM cells that is further induced by adhesion to bone marrow stromal cells (BMSC). Sp1 knockdown decreases MM cell proliferation and induces apoptosis. Sp1-DNA binding inhibition by TMP inhibits MM cell growth both in vitro and in vivo, inducing caspase-9-dependent apoptosis and overcoming the protective effects of BMSCs.
Our results show Sp1 as an important transcription factor in myeloma that can be therapeutically targeted for clinical application by TMP.
转录因子特异性蛋白 1（Sp1）通过调节包含近端 GC/GT 丰富启动子元件的关键细胞周期、分化和凋亡相关基因的表达来控制许多细胞过程。我们在此提供实验和临床证据表明，Sp1 在多发性骨髓瘤（MM）细胞生长和存活中发挥重要的调节作用。
我们使用萤火虫荧光素酶报告基因的质粒，通过 Sp1 反应性启动子驱动，研究了 MM 细胞中的功能性 Sp1 活性。我们还使用 siRNA 和短发夹 RNA 介导的 Sp1 敲低来研究 Sp1 对 MM 细胞生长和存活的影响，并进一步研究了特美普罗尔（TMP）的抗 MM 活性，TMP 是一种小分子，可在体外和体内特异性竞争 Sp1-DNA 结合。
我们已经证实 MM 细胞中 Sp1 活性较高，与骨髓基质细胞（BMSC）黏附后进一步诱导。Sp1 敲低可降低 MM 细胞增殖并诱导细胞凋亡。TMP 通过抑制 Sp1-DNA 结合抑制 MM 细胞的体外和体内生长，诱导 caspase-9 依赖性凋亡并克服 BMSC 的保护作用。
我们的结果表明 Sp1 是骨髓瘤中的一个重要转录因子，可通过 TMP 进行治疗靶向，用于临床应用。
