Martin Timothy D, Der Channing J
Deparment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Small GTPases. 2012 Apr-Jun;3(2):126-30. doi: 10.4161/sgtp.19571.
Mutationally activated K-Ras can utilize a multitude of downstream effector proteins to promote oncogenesis. While the Raf and phosphoinositol 3-kinase effector pathways are the best-studied and validated, recent studies have established the critical importance of Ral guanine nucleotide exchange factor (RalGEF) activation of the RalA and RalB small GTPases in cancer biology. Due to recent evidence that the RalGEF-Ral pathway is necessary for the tumorigenic and metastatic potential of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) tumor cells, we investigated whether or not Ral signaling was necessary for KRAS mutant colorectal cancer (CRC) tumor cell growth. As in PDAC, we found upregulated RalA and RalB activation in CRC tumor cell lines and tumors. Surprisingly we found antagonistic roles for RalA and RalB in the regulation of CRC tumor cell anchorage-independent growth. This observation contrasts with PDAC, where RalA but not RalB is necessary for PDAC tumor cell anchorage-independent growth. Our results emphasize cancer cell type differences in Ral function and hence the need for distinct Ral targeted therapeutic approaches in the treatment of CRC vs. PDAC.
突变激活的K-Ras可利用多种下游效应蛋白来促进肿瘤发生。虽然Raf和磷酸肌醇3-激酶效应途径是研究最深入且已得到验证的，但最近的研究已证实，Ral鸟嘌呤核苷酸交换因子（RalGEF）激活RalA和RalB小GTP酶在癌症生物学中至关重要。由于最近有证据表明RalGEF-Ral途径对于KRAS突变型胰腺导管腺癌（PDAC）肿瘤细胞的致瘤和转移潜能是必需的，我们研究了Ral信号对于KRAS突变型结直肠癌（CRC）肿瘤细胞生长是否必要。与PDAC一样，我们在CRC肿瘤细胞系和肿瘤中发现RalA和RalB的激活上调。令人惊讶的是，我们发现RalA和RalB在调节CRC肿瘤细胞非锚定依赖性生长中具有拮抗作用。这一观察结果与PDAC形成对比，在PDAC中，RalA而非RalB是PDAC肿瘤细胞非锚定依赖性生长所必需的。我们的结果强调了Ral功能在癌细胞类型上的差异，因此在治疗CRC与PDAC时需要不同的Ral靶向治疗方法。
