Molecular Mechanism Governing the Metabolic Reprogramming of Cancer Stem Cells in Nasopharyngeal Carcinoma

• Main Authors: Yao-An Shen, 沈耀安
• Other Authors: Yau-Huei Wei
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/08602969180713030448

博士 === 國立陽明大學 === 生化暨分子生物研究所 === 103 === Cancer stem cells (CSCs) refer to a distinct subset of tumor cells endowed with self-renewal capacity and are resistant to cancer treatment. The metabolic hallmarks of CSCs and molecular mechanisms governing their stem cell-like properties have remained elusive. To address these questions, we utilized nasopharyngeal carcinoma (NPC) CSCs as a model to investigate the characteristic hallmarks of CSC metabolism. We demonstrated that NPC CSCs experienced metabolic shift and mitochondrial resetting. In metabolic shift, CSCs showed a greater dependence on glycolysis compared with the parental cells. For mitochondrial resetting, the quantity and quality of mitochondria in CSCs were altered by the biogenesis of the organelles, and the round-shaped mitochondria were revolved around the nucleus as those observed in the normal stem cells. Moreover, the properties of CSCs were restrained when we redirected the pivotal metabolic reprogramming, which strongly supports the contention that the energy metabolism plasticity plays a role in the regulation of the equilibrium of acquisition and loss of the stemness status. Importantly, inhibition of the glycolytic pathway by 2-deoxyglucose and knockdown of lactate dehydrogenase A (LDHA) attenuated CSC properties and low concentration of glucose led to apoptosis and reduction of stemness traits. Lactate was able to halt the stagnation of stemness and epithelial-mesenchymal transition (EMT) by glucose depletion. Furthermore, lactate was found to induce the reprogramming of differentiated neoplastic cells into CSCs. Lactate also induced acetylation of lysine 56 on histone H3 (H3K56) while knockdown of ATP-citrate lyase (ACLY) attenuated the lactate effects, which suggest that lactate could be converted to acetyl-coA to enhance histone acetylation and in turn upregulated the stemness features. Intriguingly, we found that resveratrol switched off the metabolic shift, increased the reactive oxygen species (ROS) levels as well as depolarized mitochondrial membranes. These alterations of metabolic phenotype coincided with the suppression of CSC properties including therapeutic resistance, self-renewal capacity, tumor-initiating capacity, and metastatic potential in NPC CSCs. On the other hand, we discovered that resveratrol was able to impede the true kernel of CSC properties through activation of p53, and that the effect could be redirected by knockdown of p53. In addition, resveratrol curbed the stemness and EMT through reactivation of p53 to induce the expression of miR-145 and miR-200c, which were down-regulated in NPC CSCs. Moreover, miR-145 was found to block the reprogramming of NPC CSCs by inhibiting the expression of Yamanaka cocktail Oct4, Sox2, Klf4, and c-Myc. In conclusion, we demonstrated that CSCs undergo metabolic reprogramming to produce lactate to stimulate acetylation of H3K56 for upholding CSC properties and increasing their subpopulation in tumor mass. This unique metabolic signature of CSCs could be reversed by resveratrol, a natural polyphenol. Resveratrol employed the p53 pathway to impede stemness, EMT, and metabolic reprogramming of CSCs. Further investigation of the molecular mechanism of p53 activation by resveratrol may provide useful information for the development of novel therapies for cancer treatment through targeting to CSCs.