title: ECM1 promotes the Warburg effect through EGF-mediated activation of PKM2.
abstract: The Warburg effect is an oncogenic metabolic switch that allows cancer cells to take up more glucose than normal cells and favors anaerobic glycolysis. Extracellular matrix protein 1 (ECM1) is a secreted glycoprotein that is overexpressed in various types of carcinoma. Using two-dimensional digest-liquid chromatography-mass spectrometry (LC-MS)/MS, we showed that the expression of proteins associated with the Warburg effect was upregulated in trastuzumab-resistant BT-474 cells that overexpressed ECM1 compared to control cells. We further demonstrated that ECM1 induced the expression of genes that promote the Warburg effect, such as glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and hypoxia-inducible factor 1 α (HIF-1α). The phosphorylation status of pyruvate kinase M2 (PKM-2) at Ser37, which is responsible for the expression of genes that promote the Warburg effect, was affected by the modulation of ECM1 expression. Moreover, EGF-dependent ERK activation that was regulated by ECM1 induced not only PKM2 phosphorylation but also gene expression of GLUT1 and LDHA. These findings provide evidence that ECM1 plays an important role in promoting the Warburg effect mediated by PKM2.
authors.affiliation: Department of Life Science, Hanyang University, Seoul, Republic of Korea.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Department of Life Science, Hanyang University, Seoul, Republic of Korea.
authors.forename: Keesoo
authors.initials: K
authors.lastname: Nam
authors.affiliation: Department of Life Science, Hanyang University, Seoul, Republic of Korea.
authors.forename: Sunhwa
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Life Science, Hanyang University, Seoul, Republic of Korea.
authors.forename: Juyeon
authors.initials: J
authors.lastname: Lim
authors.affiliation: NOVA Cell Technology, Inc., Pohang, Republic of Korea.
authors.forename: Taehoon
authors.initials: T
authors.lastname: Lee
authors.affiliation: Department of Life Science, Hanyang University, Seoul, Republic of Korea; Natural Science Institute, Hanyang University, Seoul, Republic of Korea. Electronic address: incheol@hanyang.ac.kr.
authors.forename: Incheol
authors.initials: I
authors.lastname: Shin
mesh_terms: D045744:Cell Line, Tumor; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D010766:Phosphorylation; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: C490607:ECM1 protein, human; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D016326:Extracellular Matrix Proteins; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D011770:Pyruvate Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose
keywords: ECM1; GLUT1; LDHA; PKM2; Warburg effect