Long noncoding RNA-mediated activation of PROTOR1/PRR5-AKT signaling shunt downstream of PI3K in triple-negative breast cancer.
Long noncoding RNA-mediated activation of PROTOR1/PRR5-AKT signaling shunt downstream of PI3K in triple-negative breast cancer.
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DOI：
10.1073/pnas.2203180119
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发表时间：
2022-10-25
影响因子：
11.1
通讯作者：
Karnoub, Antoine E.
中科院分区：
文献类型：
--
作者：
Tu, Zhenbo;Hu, Yi;Raizada, Devesh;Bassal, Mahmoud A.;Tenen, Daniel G.;Karnoub, Antoine E.
磷酸肌肽3-激酶(PI3K) -AKT致癌途径在三阴性乳腺癌（tnbc）中过度激活，是这种高度侵袭性乳腺癌亚型的主要治疗靶点。不幸的是，由于不完全了解维持下游PI3K活性的代偿级联反应，PI3K途径抑制剂在TNBC患者中并未显示出明显的临床效用。在这里，我们描述了一个以前未被发现的长链非编码RNA （lncRNA）主导的前恶性通路，它本身是PI3K-AKT的下游靶点，并且作为一个正反馈分流，促进AKT独立于PI3K的激活。我们证明了这种lncRNA作为TNBC生长的决定因素的关键作用，并强调了它作为TNBC治疗中有吸引力的治疗靶点的潜力。磷酸肌肽3-激酶（PI3K）途径是三阴性乳腺癌（TNBC）中最亢奋的致癌途径，TNBC是一种高度侵袭性的肿瘤亚型，约占乳腺癌的15%，目前尚无靶向治疗方法。尽管PI3K通路抑制剂的信号臂在疾病发病机制中发挥了重要作用，但由于对PI3K下游的代偿级联反应的理解仍然不完整，PI3K通路抑制剂在TNBC中没有达到预期的临床反应。在这里，我们研究了长链非编码rna （lncRNAs）在临床和实验TNBC中对PI3K活性的贡献，并发现LINC01133作为PI3K- akt信号效应物的突出作用。我们发现LINC01133在TNBC中发挥了致蛋白作用，并且它控制了先前描述的mTOR复合物2 （mTORC2）依赖途径，该途径以不依赖pi3k的方式激活AKT。机制上，LINC01133通过竞争性偶联其负信使RNA （mRNA）调节剂异质核核糖核蛋白A2/B1 （hnRNPA2B1）诱导mTORC2组分PROTOR1/PRR5的表达。反过来，PROTOR1/PRR5对于linc01133触发的功能是充分和必要的，揭示了该rictor结合蛋白在细胞信号传导和生长中的先前未被认识到的作用。值得注意的是，LINC01133拮抗剂破坏了细胞生长，我们发现LINC01133- protor1 /PRR5通路与TNBC患者生存不良密切相关。总之，我们的研究结果揭示了lncrna驱动的信号转导，它是PI3K通路下游恶性肿瘤的关键决定因素，也是临床TNBC管理中潜在的RNA治疗靶点。
The phosphoinositide 3-kinase (PI3K)–AKT oncogenic pathway is hyperactivated in triple-negative breast cancers (TNBCs) and represents a prime therapeutic target in this highly aggressive breast tumor subtype. Unfortunately, PI3K pathway inhibitors have not shown overt clinical utility in TNBC patients due in part to incompletely understood compensatory cascades that sustain downstream PI3K activities. Here, we describe a previously unappreciated long noncoding RNA (lncRNA)–led promalignant pathway that is itself a downstream target of PI3K-AKT and that additionally functions as a positive feedback shunt that fosters AKT activation independent of PI3K. We demonstrate this lncRNA’s critical role as a determinant of TNBC growth and highlight its potential as an attractive therapeutic target in TNBC management. The phosphoinositide 3-kinase (PI3K) pathway represents the most hyperactivated oncogenic pathway in triple-negative breast cancer (TNBC), a highly aggressive tumor subtype encompassing ∼15% of breast cancers and which possesses no targeted therapeutics. Despite critical contributions of its signaling arms to disease pathogenesis, PI3K pathway inhibitors have not achieved expected clinical responses in TNBC, owing largely to a still-incomplete understanding of the compensatory cascades that operate downstream of PI3K. Here, we investigated the contributions of long noncoding RNAs (lncRNAs) to PI3K activities in clinical and experimental TNBC and discovered a prominent role for LINC01133 as a PI3K-AKT signaling effector. We found that LINC01133 exerted protumorigenic roles in TNBC and that it governed a previously undescribed mTOR Complex 2 (mTORC2)–dependent pathway that activated AKT in a PI3K-independent manner. Mechanistically, LINC01133 induced the expression of the mTORC2 component PROTOR1/PRR5 by competitively coupling away its negative messenger RNA (mRNA) regulator, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1). PROTOR1/PRR5 in turn was sufficient and necessary for LINC01133-triggered functions, casting previously unappreciated roles for this Rictor-binding protein in cellular signaling and growth. Notably, LINC01133 antagonism undermined cellular growth, and we show that the LINC01133-PROTOR1/PRR5 pathway was tightly associated with TNBC poor patient survival. Altogether, our findings uncovered a lncRNA-driven signaling shunt that acts as a critical determinant of malignancy downstream of the PI3K pathway and as a potential RNA therapeutic target in clinical TNBC management.
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影响因子：
7.3
作者：
Clement E;Inuzuka H;Nihira NT;Wei W;Toker A
通讯作者：
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影响因子：
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影响因子：
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作者：
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影响因子：
4.8
作者：
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通讯作者：
Thiele, BJ
DOI：
10.1038/s41580-020-00315-9
发表时间：
2021-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Statello L;Guo CJ;Chen LL;Huarte M
通讯作者：
Huarte M