小柯机器人

英国比森癌症研究所Owen J. Sansom研究小组的最新研究发现，氨基酸转运蛋白SLC7A5对于KRAS突变大肠癌（CRC）细胞的生长至关重要。相关论文发表在2021年1月7日出版的《自然-遗传学》杂志上。

研究发现小鼠肠上皮细胞中Apc和Kras突变会显著影响新陈代谢，增加谷氨酰胺的消耗。

此外，SLC7A5（一种谷氨酰胺逆转运蛋白）对于早期和晚期转移性疾病模型中结直肠肿瘤的发生均至关重要。从机制上讲，SLC7A5在KRAS激活后通过转录和代谢重编程来维持细胞内氨基酸水平。这对于癌细胞蛋白质合成需求的增加和 KRAS突变细胞增殖的增强至关重要。

此外，通过抑制mTORC1调节因子和Slc7a5缺失来抑制蛋白质合成可以减弱Kras突变型肿瘤的生长。总之，这些数据表明SLC7A5是治疗KRAS突变CRC的潜在靶点。

据了解，大肠癌中同时发生致癌性KRAS突变和APC肿瘤抑制因子的失活。尽管科学家努力研发直接靶向KRAS突变体的药物，但大多数治疗方法都集中在下游途径上，因而疗效有限。此外， KRAS突变改变了癌细胞的基础代谢，增加了谷氨酰胺的利用来维持细胞增殖。

附：英文原文

Title: The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer

Author: Arafath K. Najumudeen, Fatih Ceteci, Sigrid K. Fey, Gregory Hamm, Rory T. Steven, Holly Hall, Chelsea J. Nikula, Alex Dexter, Teresa Murta, Alan M. Race, David Sumpton, Nikola Vlahov, David M. Gay, John R. P. Knight, Rene Jackstadt, Joshua D. G. Leach, Rachel A. Ridgway, Emma R. Johnson, Colin Nixon, Ann Hedley, Kathryn Gilroy, William Clark, Sudhir B. Malla, Philip D. Dunne, Giovanny Rodriguez-Blanco, Susan E. Critchlow, Agata Mrowinska, Gaurav Malviya, Dmitry Solovyev, Gavin Brown, David Y. Lewis, Gillian M. Mackay, Douglas Strathdee, Saverio Tardito, Eyal Gottlieb, Zoltan Takats, Simon T. Barry, Richard J. A. Goodwin, Josephine Bunch, Martin Bushell, Andrew D. Campbell, Owen J. Sansom

Issue&Volume: 2021-01-07

Abstract: Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras-mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC. Colorectal tumors with mutated KRAS and APC require the amino acid transporter SLC7A5 to drive tumorigenesis. Mechanistically, SLC7A5 drives transcriptional and metabolic reprogramming by maintaining intracellular amino acid levels, leading to enhanced protein synthesis.

DOI: 10.1038/s41588-020-00753-3

Source: https://www.nature.com/articles/s41588-020-00753-3

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex