Activation and involvement of Ral GTPases in colorectal cancer.
Activation and involvement of Ral GTPases in colorectal cancer.
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RAL GTPases在大肠癌中的激活和参与。
DOI：
10.1158/0008-5472.can-10-1517
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发表时间：
2011-01-01
期刊：
影响因子：
11.2
通讯作者：
Yeh JJ
中科院分区：
文献类型：
--
作者：
Martin TD;Samuel JC;Routh ED;Der CJ;Yeh JJ
目前阻断KRAS癌基因功能的方法主要集中在抑制K-RAS下游效应信号。我们评价了一种有效和选择性的MEK1/2抑制剂塞鲁米替尼(AZD6244ARRY-142886)对一组结直肠癌细胞的抗肿瘤活性，发现对KRAS突变型结直肠癌细胞的锚定非依赖性生长没有抑制作用。虽然在KRAS突变细胞中AKT活性升高，并且抑制PI3K确实损害了MEK抑制剂不敏感的CRC细胞系的生长，但与selumetinib同时处理并没有提供额外的抗肿瘤活性。因此，我们推测，抑制RalGen交换因子效应通路可能是阻断结直肠癌生长的更有效途径。RalGEF是相关的Rala和RalB小GTP酶的激活物，我们发现两者在结直肠癌细胞系和患者肿瘤中都有激活。干扰RNA稳定抑制Rala的表达降低了结直肠癌细胞的贴壁非依赖性生长，但令人惊讶的是，稳定抑制RalB大大提高了软琼脂集落大小和形成频率。尽管RalA和RalB的活性相反，但Rala和RalB对锚定非依赖性生长的调控都需要与RalBP1/RLIP76和胞囊复合体的组成部分相互作用。有趣的是，Rala与Exo84而不是Sec5胞囊成分的相互作用是支持锚定非依赖性生长所必需的，而RalB与Sec5而不是Exo84相互作用是抑制锚定非依赖性生长所必需的。我们认为，抗RAA选择性治疗可能为KRAS突变型CRC提供一种有效的治疗方法。
Current approaches to block KRAS oncogene function focus on inhibition of K-Ras downstream effector signaling. We evaluated the anti-tumor activity of selumetinib (AZD6244, ARRY-142886), a potent and selective MEK1/2 inhibitor, on a panel of colorectal carcinoma (CRC) cells and found no inhibition of KRAS mutant CRC cell anchorage-independent growth. While AKT activity was elevated in KRAS mutant cells, and PI3K inhibition did impair the growth of MEK inhibitor-insensitive CRC cell lines, concurrent treatment with selumetinib did not provide additional anti-tumor activity. Therefore, we speculated that inhibition of the Ral guanine exchange factor (RalGEF) effector pathway may be a more effective approach for blocking CRC growth. RalGEFs are activators of the related RalA and RalB small GTPases and we found activation of both in CRC cell lines and patient tumors. Interfering RNA stable suppression of RalA expression reduced CRC tumor cell anchorage-independent growth, but surprisingly, stable suppression of RalB greatly enhanced soft agar colony size and formation frequency. Despite their opposing activities, both RalA and RalB regulation of anchorage-independent growth required interaction with RalBP1/RLIP76 and components of the exocyst complex. Interestingly, RalA interaction with the Exo84 but not Sec5 exocyst component was necessary for supporting anchorage-independent growth, whereas RalB interaction with Sec5 but not Exo84 was necessary for inhibition of anchorage-independent growth. We suggest that anti-RalA-selective therapies may provide an effective approach for KRAS mutant CRC.