Witherspoon Mavee, Sandu Davinder, Lu Changyuan, Wang Kehui, Edwards Robert, Yeung Anthony, Gelincik Ozkan, Manfredi Giovanni, Gross Steven, Kopelovich Levy, Lipkin Steven
Department of Medicine, Weill Cornell College of Medicine, New York, NY, USA.
Department of Pharmacology, Weill Cornell College of Medicine, New York, NY, USA.
Oncotarget. 2019 Jun 18;10(40):4004-4017. doi: 10.18632/oncotarget.26958.
Ethylmalonic Encephalopathy Protein 1 () is a sulfur dioxygenase that regulates cellular HS levels. We previously demonstrated a significant increase of expression in "single-hit" colon epithelial cells from crypts of patients with Familial Adenomatous Polyposis (FAP). Here, we report elevated levels of expression and increased mitochondrial density occurring in-situ in phenotypically normal FAP colorectal mucosa. We also found that constitutive expression of increased aerobic glycolysis ("Warburg effect"), oxidative phosphorylation, and mitochondrial biogenesis in colorectal cancer (CRC) cell lines, thereby depleting HS which relieved the inhibition of phosphodiesterase (PDE), and increased adenosine monophosphate (AMP) levels. This led to activation of the energy sensing AMP-activated protein kinase (AMPKp), Sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), a master regulator of mitochondrial biogenesis. By contrast, shRNA silencing of reduced PDE activity, AMPKp/SIRT1/PGC1α levels and mitochondrial biogenesis. Constitutive expression of accelerated both CRC cell xenograft and orthotopic patient derived xenograft CRC cell growth . Overall, our data nominate elevated as a novel biomarker and potential therapeutic target for the prevention of CRC tumorigenesis.
乙基丙二酸脑病蛋白1（）是一种调节细胞内硫化氢（HS）水平的硫双加氧酶。我们之前证明，在家族性腺瘤性息肉病（FAP）患者隐窝的“单次打击”结肠上皮细胞中，该蛋白的表达显著增加。在此，我们报告在表型正常的FAP结直肠黏膜中原位出现该蛋白表达水平升高以及线粒体密度增加。我们还发现，该蛋白的组成性表达增加了结直肠癌（CRC）细胞系中的有氧糖酵解（“瓦伯格效应”）、氧化磷酸化和线粒体生物发生，从而消耗了硫化氢，解除了对磷酸二酯酶（PDE）的抑制，并增加了单磷酸腺苷（AMP）水平。这导致能量感应的AMP激活蛋白激酶（AMPKp）、沉默调节蛋白1（SIRT1）和过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α，线粒体生物发生的主要调节因子）被激活。相比之下，该蛋白的短发夹RNA（shRNA）沉默降低了PDE活性、AMPKp/SIRT1/PGC1α水平以及线粒体生物发生。该蛋白的组成性表达加速了CRC细胞异种移植和原位患者来源的异种移植CRC细胞的生长。总体而言，我们的数据表明该蛋白表达升高是预防CRC肿瘤发生的一种新型生物标志物和潜在治疗靶点。
