LARP1 regulates metabolism and mTORC1 activity in cancer-猫眼课题宝

DOI：

10.1101/2022.09.04.506559

发表时间：

2022-09

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

James Chettle;Z. Dedeic;R. Fischer;I. Vendrell;L. Campo;A. Easton;Molly Browne;Josephine L Morris;Hagen Schwenzer;P. Lascaux;R. Gijsbers;Elisabete Pires;D. Royston;David J. P. Ferguson;A. Coosemans;B. Kessler;J. McCullagh;A. Ahmed;Kristijan Ramadan;M. Bushell;A. Harris;C. Goding;S. Blagden

哺乳动物雷帕霉素靶蛋白 (mTOR) 是细胞稳态的主要调节因子。尽管 mTOR 在 70% 的卵巢癌中异常过度激活，但 mTOR 级联抑制剂（例如阻断 mTOR 本身激酶活性或上游激酶 PI3K/AKT 的抑制剂）在卵巢癌临床试验中表现出令人失望的活性。这些发现表明，尽管过度激活的 mTOR 在正常细胞中发挥着关键作用，但在这种癌症背景下，它并不能充当代谢的主要调节因子。令人惊讶的是，我们发现 RNA 结合蛋白 LARP1（一种已知的 mTORC1 磷酸靶标和核糖体生物合成激活剂）负责 mTOR 失调癌症中的代谢重编程。 LARP1 转录后调节数百种限速酶的表达，这些限速酶涉及代谢的多个方面，包括糖酵解和氧化磷酸化。通过这种机制，LARP1 维持 ATP 产生和 mTORC1 在溶酶体上的定位，从而在细胞外营养物质匮乏的情况下激活细胞增殖。我们的研究结果表明，通过维持全球细胞代谢以响应生长因子信号传导，LARP1 在控制 mTORC1 定位和驱动癌症进展（这是癌症的一个关键标志）方面发挥着核心转录后作用。

The protein mammalian target of rapamycin (mTOR) is a master regulator of cell homeostasis. Although mTOR is aberrantly overactivated in 70% ovarian cancers, mTOR cascade inhibitors (such as those blocking the kinase activity of mTOR itself or upstream kinases PI3K/AKT) have demonstrated disappointing activity in ovarian cancer clinical trials. These findings indicate that, despite its pivotal role in normal cells, hyperactivated mTOR does not act as a master regulator of metabolism in this cancer context. Surprisingly, we have identified that the RNA binding protein LARP1, a known phospho-target of mTORC1 and activator of ribosomal biogenesis, is responsible for metabolic reprogramming in mTOR-dysregulated cancers. LARP1 post-transcriptionally regulates the expression of several hundred rate-limiting enzymes involved in multiple aspects of metabolism, including glycolysis and oxidative phosphorylation. Through this mechanism LARP1 sustains ATP production and mTORC1 localisation on the lysosome, thereby activating cell proliferation despite the scarcity of extracellular nutrients. Our findings show that, by sustaining global cellular metabolism in response to growth factor signalling, LARP1 has a central post-transcriptional role in controlling mTORC1 localisation and driving cancer progression, a key cancer hallmark.

LARP1 regulates metabolism and mTORC1 activity in cancer

文献摘要

相似文献