Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Pigment Cell Melanoma Res. 2013 Jan;26(1):97-112. doi: 10.1111/pcmr.12031. Epub 2012 Nov 6.
CDDO-Me has been shown to exert potent anti-inflammatory activity for chronic kidney disease and antitumor activity for several tumors, including melanoma, in early clinical trials. To improve CDDO-Me response in melanoma, we utilized a large-scale synthetic lethal RNAi screen targeting 6000 human druggable genes to identify targets that would sensitize melanoma cells to CDDO-Me. Based on screening results, five unique genes (GNPAT, SUMO1, SPINT2, FLI1, and SSX1) significantly potentiated the growth inhibitory effects of CDDO-Me and induced apoptosis in A375, a BRAF mutated melanoma line (P < 0.001). These five genes were then individually validated as targets to potentiate CDDO-Me activity, and related downstream signaling pathways of these genes were analyzed. In addition, the levels of phosphorylated Erk1/2, Akt, GSK-2, and PRAS40 were dramatically decreased by downregulating each of these five genes separately, suggesting a set of common mediators. Our findings indicate that GNPAT, SUMO1, SPINT2, FLI1, and SSX1 play critical roles in synergy with inflammation pathways in modulating melanoma cell survival and could serve as sensitizing targets to enhance CDDO-Me efficacy in melanoma growth control.
CDDO-Me 已被证明在慢性肾病中具有强大的抗炎活性，并在早期临床试验中对几种肿瘤（包括黑色素瘤）具有抗肿瘤活性。为了提高黑色素瘤对 CDDO-Me 的反应，我们利用针对 6000 个人类可用药基因的大规模合成致死 RNAi 筛选，以鉴定可使黑色素瘤细胞对 CDDO-Me 敏感的靶标。基于筛选结果，五个独特的基因（GNPAT、SUMO1、SPINT2、FLI1 和 SSX1）显著增强了 CDDO-Me 的生长抑制作用，并诱导 BRAF 突变黑色素瘤系 A375 细胞凋亡（P<0.001）。然后将这五个基因分别单独验证为增强 CDDO-Me 活性的靶标，并分析了这些基因的相关下游信号通路。此外，下调这五个基因中的每一个都显著降低了磷酸化 Erk1/2、Akt、GSK-2 和 PRAS40 的水平，表明存在一组共同的介质。我们的研究结果表明，GNPAT、SUMO1、SPINT2、FLI1 和 SSX1 在与炎症通路协同作用调节黑色素瘤细胞存活方面发挥着关键作用，可作为增敏靶点，增强 CDDO-Me 在黑色素瘤生长控制中的疗效。
