ROS-independent ER stress-mediated NRF2 activation promotes warburg effect to maintain stemness-associated properties of cancer-initiating cells

• DOI: 10.1038/s41419-017-0250-x
• Publication Date: 2018-02-07T17:08:28Z
• Authors: Ching-Wen Chang; Yu-Syuan Chen; Yeou-Guang Tsay; Chia-Li Han; Yu-Ju Chen; Cheng-Chieh Yang; Kai-Feng Hung; Chao-Hsiung Lin; Tsung-Yen Huang; Shou-Yen Kao; Te-Chang Lee; Jeng-Fan Lo
• Keywords: Warburg Effect

Cancer-initiating cells (CICs) are responsible for tumor initiation, progression, and therapeutic resistance; moreover, redox homeostasis is important in regulating cancer stemness. Previously, we have identified that containing low intracellular reactive oxygen species levels (ROSLow cells) display enhanced features of CICs. However, the specific metabolic signatures CICs remain unclear required further characterization by systemic screenings. Herein, first showed mainly relying on glycolysis was maintenance stemness properties. Next, revealed NRF2, a master regulator antioxidants, able to maintain ROS CICs, even though absence oxidative stress. We characterized NRF2 activation Of ROSLow cells, not only directly activates transcription genes encoding glycolytic enzymes but also inhibited conversion pyruvate acetyl-CoA activating dehydrogenase kinase 1 (PDK1) lead inhibition tricarboxylic acid (TCA) cycle; therefore, promote Warburg effect. A positive regulatory ROS-independent ER stress pathway (GRP78/p-PERK/NRF2 signaling) mediate shift (Warburg effect) Lastly, co-expression p-PERK p-NRF2 significantly associated with clinical outcome. Our data show acting as central node properties which outcome, independent from Future treatments inhibiting may exhibit great potential targeting