Vora Mehul, Mondal Arindam, Jia Dongxuan, Gaddipati Pranya, Akel Moumen, Gilleran John, Roberge Jacques, Rongo Christopher, Langenfeld John
Department of Genetics, The Waksman Institute, Rutgers the State University of NJ, Piscataway, NJ, 08854, USA.
Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08903, USA.
Cell Biosci. 2022 May 31;12(1):76. doi: 10.1186/s13578-022-00817-3.
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.
骨形态发生蛋白（BMP）是一种在进化上保守的信号通路，对发育至关重要，在包括癌症、阿尔茨海默病、肥胖症和心血管疾病在内的几种与年龄相关的疾病中异常表达。小鼠中异常的BMP信号传导会导致肥胖，这表明它可能会改变正常代谢。BMP信号传导对癌症代谢的调节作用尚不清楚。
为了研究BMP对代谢的调节作用，利用蛋白质免疫印迹分析和荧光报告基因，检测了携带BMP功能获得性（gof）和功能丧失性（lof）突变的秀丽隐杆线虫在分解代谢和合成代谢活性方面的变化。使用AMP激活激酶（AMPK）的gof和lof突变体来研究AMPK对BMP信号传导的调节。使用H1299（LKB1野生型）、A549（LKB1 lof）和A549-LKB1（LKB1恢复型）肺癌细胞系来研究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小干扰RNA（siRNA）抑制信号传导。
秀丽隐杆线虫和癌细胞中的BMP信号传导对营养状况有反应。在秀丽隐杆线虫和肺癌细胞系中，BMP均抑制分解代谢的主要调节因子AMPK，同时激活合成代谢的调节因子PI3K。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，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配体降低了H1299细胞中三羧酸循环中间产物和非必需氨基酸的表达。此外，我们表明PI3K的BMP激活是通过BMP II型受体介导的。我们还观察到反馈信号，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信号传导产生负调节，而合成代谢信号通过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。
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