Bone morphogenetic protein signaling regulation of AMPK and PI3K in lung cancer cells and C. elegans.
Bone morphogenetic protein signaling regulation of AMPK and PI3K in lung cancer cells and C. elegans.
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肺癌细胞和秀丽隐杆线虫中AMPK和PI3K的骨形态发生蛋白信号传导调节。
DOI：
10.1186/s13578-022-00817-3
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发表时间：
2022-05-31
影响因子：
7.5
通讯作者：
Langenfeld, John
中科院分区：
文献类型：
--
作者：
Vora, Mehul;Mondal, Arindam;Jia, Dongxuan;Gaddipati, Pranya;Akel, Moumen;Gilleran, John;Roberge, Jacques;Rongo, Christopher;Langenfeld, John
骨形态发生蛋白 (BMP) 是发育所需的系统发育保守信号通路，在多种与年龄相关的疾病中异常表达，包括癌症、阿尔茨海默病、肥胖和心血管疾病。小鼠体内 BMP 信号异常会导致肥胖，这表明它可能会改变正常的新陈代谢。 BMP 信号传导调节癌症代谢的作用尚不清楚。为了检查 BMP 对代谢的调节，利用蛋白质印迹分析和荧光报告仪检查了携带 BMP 功能获得 (gof) 和功能丧失 (lof) 突变的线虫的分解代谢和合成代谢活性的变化。 AMP 激活激酶 (AMPK) gof 和 lof 突变体用于检查 BMP 信号传导的 AMPK 调节。 H1299（LKB1 野生型）、A549（LKB1 lof）和 A549-LKB1（LKB1 恢复）肺癌细胞系用于研究 BMP 对分解代谢和合成代谢的调节。研究使用重组 BMP 配体激活 BMP 信号传导，并使用 BMP 受体特异性抑制剂和 siRNA 抑制信号传导。线虫和癌细胞中的 BMP 信号传导对营养条件有反应。在秀丽隐杆线虫和肺癌细胞系中，BMP 抑制 AMPK（分解代谢的主要调节因子），同时激活 PI3K（合成代谢的调节因子）。在肺癌细胞中，通过 siRNA 或小分子抑制 BMP 信号传导会增加 AMPK 活性，而这种增加是由 LKB1 的激活介导的。 BMP2 配体在饥饿期间抑制 AMPK 激活。 BMP2配体降低H1299细胞中TCA循环中间体和非必需氨基酸的表达。此外，我们发现 BMP 对 PI3K 的激活是通过 BMP II 型受体介导的。我们还观察到反馈信号传导，因为 AMPK 抑制 BMP 信号传导，而 PI3K 增加 BMP 信号传导。这些研究表明 BMP 信号传导抑制分解代谢并刺激合成代谢。我们确定了反馈机制，其中由 AMPK 介导的分解代谢诱导信号对 BMP 信号产生负调节，而合成代谢信号则通过 Akt 对 BMP 信号产生正反馈调节。这些机制在肺癌细胞和秀丽隐杆线虫中都是保守的。这些研究表明，异常的 BMP 信号传导会导致代谢失调，这是 BMP 促进癌细胞存活的潜在机制。
Bone morphogenetic protein (BMP) is a phylogenetically conserved signaling pathway required for development that is aberrantly expressed in several age-related diseases including cancer, Alzheimer’s disease, obesity, and cardiovascular disease. Aberrant BMP signaling in mice leads to obesity, suggesting it may alter normal metabolism. The role of BMP signaling regulating cancer metabolism is not known. To examine BMP regulation of metabolism, C. elegans harboring BMP gain-of-function (gof) and loss-of-function (lof) mutations were examined for changes in activity of catabolic and anabolic metabolism utilizing Western blot analysis and fluorescent reporters. AMP activated kinase (AMPK) gof and lof mutants were used to examine AMPK regulation of BMP signaling. H1299 (LKB1 wild-type), A549 (LKB1 lof), and A549-LKB1 (LKB1 restored) lung cancer cell lines were used to study BMP regulation of catabolic and anabolic metabolism. Studies were done using recombinant BMP ligands to activate BMP signaling, and BMP receptor specific inhibitors and siRNA to inhibit signaling. BMP signaling in both C. elegans and cancer cells is responsive to nutrient conditions. In both C. elegans and lung cancer cell lines BMP suppressed AMPK, the master regulator of catabolism, while activating PI3K, a regulator of anabolism. In lung cancer cells, inhibition of BMP signaling by siRNA or small molecules increased AMPK activity, and this increase was mediated by activation of LKB1. BMP2 ligand suppressed AMPK activation during starvation. BMP2 ligand decreased expression of TCA cycle intermediates and non-essential amino acids in H1299 cells. Furthermore, we show that BMP activation of PI3K is mediated through BMP type II receptor. We also observed feedback signaling, as AMPK suppressed BMP signaling, whereas PI3K increased BMP signaling. These studies show that BMP signaling suppresses catabolic metabolism and stimulates anabolic metabolism. We identified feedback mechanisms where catabolic induced signaling mediated by AMPK negatively regulates BMP signaling, whereas anabolic signaling produces a positive feedback regulation of BMP signing through Akt. These mechanisms were conserved in both lung cancer cells and C. elegans. These studies suggest that aberrant BMP signaling causes dysregulation of metabolism that is a potential mechanism by which BMP promotes survival of cancer cells.
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