Lee Kyung-Min, Nam Keesoo, Oh Sunhwa, Lim Juyeon, Lee Taehoon, Shin Incheol
Department of Life Science, Hanyang University, Seoul, Republic of Korea.
NOVA Cell Technology, Inc., Pohang, Republic of Korea.
Cell Signal. 2015 Feb;27(2):228-35. doi: 10.1016/j.cellsig.2014.11.004. Epub 2014 Nov 11.
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.
瓦伯格效应是一种致癌代谢开关，它使癌细胞比正常细胞摄取更多葡萄糖，并倾向于无氧糖酵解。细胞外基质蛋白1（ECM1）是一种分泌型糖蛋白，在多种类型的癌症中过表达。通过二维消化-液相色谱-质谱联用（LC-MS）/MS，我们发现与瓦伯格效应相关的蛋白质表达在过表达ECM1的曲妥珠单抗耐药BT-474细胞中相对于对照细胞上调。我们进一步证明，ECM1诱导促进瓦伯格效应的基因表达，如葡萄糖转运蛋白1（GLUT1）、乳酸脱氢酶A（LDHA）和缺氧诱导因子1α（HIF-1α）。负责促进瓦伯格效应的基因表达的丙酮酸激酶M2（PKM-2）在Ser37处的磷酸化状态受ECM1表达调节的影响。此外，由ECM1调节的表皮生长因子（EGF）依赖性细胞外信号调节激酶（ERK）激活不仅诱导PKM2磷酸化，还诱导GLUT1和LDHA的基因表达。这些发现提供了证据，表明ECM1在促进由PKM2介导的瓦伯格效应中起重要作用。
