Taoka Rikiya, Jinesh Goodwin G, Xue Wenrui, Safe Stephen, Kamat Ashish M
Department of Urology, Unit 1373, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA.
Apoptosis. 2017 May;22(5):719-729. doi: 10.1007/s10495-017-1359-1.
Cancer stem cells are capable of undergoing cellular transformation after commencement of apoptosis through the blebbishield emergency program in a VEGF-VEGFR2-dependent manner. Development of therapeutics targeting the blebbishield emergency program would thus be important in cancer therapy. Specificity protein 1 (Sp1) orchestrates the transcription of both VEGF and VEGFR2; hence, Sp1 could act as a therapeutic target. Here, we demonstrate that CFDODA-Me induced apoptosis, degraded Sp1, inhibited the expression of multiple drivers of the blebbishield emergency program such as VEGFR2, p70S6K, and N-Myc through activation of caspase-3, inhibited reactive oxygen species; and inhibited K-Ras activation to abolish transformation from blebbishields as well as transformation in soft agar. These findings confirm CFDODA-Me as a potential therapeutic candidate that can induce apoptosis and block transformation from blebbishields.
癌症干细胞能够在凋亡开始后，通过气泡护盾应急程序以血管内皮生长因子-血管内皮生长因子受体2（VEGF-VEGFR2）依赖的方式进行细胞转化。因此，开发针对气泡护盾应急程序的疗法在癌症治疗中具有重要意义。特异性蛋白1（Sp1）协调VEGF和VEGFR2的转录；因此，Sp1可作为治疗靶点。在此，我们证明CFDODA-Me诱导凋亡、降解Sp1、通过激活半胱天冬酶-3抑制气泡护盾应急程序的多个驱动因子如VEGFR2、p70S6K和N-Myc的表达、抑制活性氧；并抑制K-Ras激活以消除气泡护盾的转化以及软琼脂中的转化。这些发现证实CFDODA-Me是一种潜在的治疗候选物，可诱导凋亡并阻止气泡护盾的转化。
