Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion.
Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion.
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DOI：
10.7554/elife.66721
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发表时间：
2021-09-30
期刊：
影响因子：
7.7
通讯作者：
Kikuchi A
中科院分区：
文献类型：
--
作者：
Harada A;Matsumoto S;Yasumizu Y;Shojima K;Akama T;Eguchi H;Kikuchi A
胰腺癌由于转移而具有高死亡率。尽管大多数胰腺癌患者的KRAS都发生了突变，但控制KRAS或其下游效应物在临床上尚未成功。ARL 4C是一种小G蛋白，其表达由Wnt和EGF-RAS途径诱导。在本研究中，我们发现ARL 4C在胰腺癌患者中经常过表达，并表明其定位于侵袭性伪足是癌细胞侵袭所必需的。IQGAP 1是一种新的ARL 4C相互作用蛋白。ARL 4C将IQGAP 1及其下游效应物MMP 14募集到侵入性伪足中。ARL 4C、IQGAP 1和MMP 14的特异性定位是侵袭的活性位点，其诱导细胞外基质的降解。此外，皮下注射ARL 4C反义寡核苷酸抑制胰腺癌的转移。这些结果表明，ARL 4C-IQGAP 1-MMP 14信号在胰腺癌细胞的侵袭性伪足处被激活。大多数胰腺癌病例是在晚期发现的，那时很难治疗，因此生存率很低。超过90%的胰腺癌含有增加称为KRAS的蛋白质活性的遗传变化。这种过度活跃的KRAS驱动癌症的生长和进展。迄今为止，使用降低KRAS活性的药物治疗胰腺癌的尝试都失败了。KRAS蛋白可以加速健康细胞和癌症细胞的生长，它通过激活各种其他蛋白质来实现这一点。靶向这些其他蛋白质的药物可能比靶向KRAS的药物更有效地治疗胰腺癌。其中一个潜在的目标被称为ARL 4C。ARL 4C在胎儿发育期间是活跃的，但它通常不存在于成人组织中。Harada等人研究了这种蛋白质在胰腺癌中是否重要，以及它在体内的其他作用，以更好地了解它是否是癌症治疗的良好靶点。首先，Harada等人使用在实验室中生长的细胞来证明ARL 4C有助于人类胰腺癌的侵袭性扩散。Harada等人还使用小鼠表明，阻断胰腺癌中ARL 4C的活性有助于减缓其进展。Harada等人'研究结果表明，ARL 4C可能是治疗胰腺癌新药的良好靶点。鉴于这种蛋白质在成人细胞中似乎没有重要作用，因此靶向它不太可能产生重大副作用。在更类似人类的动物模型中对ARL 4C的进一步研究将有助于证实这些结果。
Pancreatic cancer has a high mortality rate due to metastasis. Whereas KRAS is mutated in most pancreatic cancer patients, controlling KRAS or its downstream effectors has not been succeeded clinically. ARL4C is a small G protein whose expression is induced by the Wnt and EGF–RAS pathways. In the present study, we found that ARL4C is frequently overexpressed in pancreatic cancer patients and showed that its localization to invasive pseudopods is required for cancer cell invasion. IQGAP1 was identified as a novel interacting protein for ARL4C. ARL4C recruited IQGAP1 and its downstream effector, MMP14, to invasive pseudopods. Specific localization of ARL4C, IQGAP1, and MMP14 was the active site of invasion, which induced degradation of the extracellular matrix. Moreover, subcutaneously injected antisense oligonucleotide against ARL4C into tumor-bearing mice suppressed metastasis of pancreatic cancer. These results suggest that ARL4C–IQGAP1–MMP14 signaling is activated at invasive pseudopods of pancreatic cancer cells. Most cases of pancreatic cancer are detected in the later stages when they are difficult to treat and, as a result, survival is low. Over 90% of pancreatic cancers contain genetic changes that increase the activity of a protein called KRAS. This hyperactive KRAS drives cancer growth and progression. Attempts to treat pancreatic cancer using drugs that reduce the activity of KRAS have so far failed. The KRAS protein can accelerate growth in healthy cells as well as in cancer and it does this by activating various other proteins. Drugs that target some of these other proteins could be more effective at treating pancreatic cancer than the drugs that target KRAS. One of these potential targets is called ARL4C. ARL4C is active during fetal development, but it is often not present in adult tissues. Harada et al. investigated whether the protein is important in pancreatic cancer, and what other roles it has in the body, to better understand if it is a good target for cancer treatment. First, Harada et al. used cells grown in the lab to show that ARL4C contributes to the aggressive spread of human pancreatic cancers. Using mice, Harada et al. also showed that blocking the activity of ARL4C in pancreatic cancers helped to slow their progression. Harada et al.’s results suggest that ARL4C could be a good target for new drugs treating pancreatic cancers. Given that this protein does not seem to have important roles in the cells of adults, targeting it is unlikely to have major side effects. Further investigation of ARL4C in more human-like animal models will help to confirm these results.