1] State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China [2] Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cell Death Differ. 2014 Jan;21(1):124-35. doi: 10.1038/cdd.2013.131. Epub 2013 Oct 4.
Side population (SP) cells within tumors are a small fraction of cancer cells with stem-like properties that can be identified by flow cytometry analysis based on their high ability to export certain compounds such as Hoechst 33342 and chemotherapeutic agents. The existence of stem-like SP cells in tumors is considered as a key factor contributing to drug resistance, and presents a major challenge in cancer treatment. Although it has been recognized for some time that tumor tissue niches may significantly affect cancer stem cells (CSCs), the role of key nutrients such as glucose in the microenvironment in affecting stem-like cancer cells and their metabolism largely remains elusive. Here we report that SP cells isolated from human cancer cells exhibit higher glycolytic activity compared to non-SP cells. Glucose in the culture environment exerts a profound effect on SP cells as evidenced by its ability to induce a significant increase in the percentage of SP cells in the overall cancer cell population, and glucose starvation causes a rapid depletion of SP cells. Mechanistically, glucose upregulates the SP fraction through ATP-mediated suppression of AMPK and activation of the Akt pathway, leading to elevated expression of the ATP-dependent efflux pump ABCG2. Importantly, inhibition of glycolysis by 3-BrOP significantly reduces SP cells in vitro and impairs their ability to form tumors in vivo. Our data suggest that glucose is an essential regulator of SP cells mediated by the Akt pathway, and targeting glycolysis may eliminate the drug-resistant SP cells with potentially significant benefits in cancer treatment.
肿瘤中的侧群 (SP) 细胞是一小部分具有干细胞样特性的癌细胞，可以通过基于其高能力将某些化合物（如 Hoechst 33342 和化疗药物）排出的流式细胞术分析来识别。肿瘤中具有干细胞样 SP 细胞的存在被认为是导致耐药性的关键因素，并在癌症治疗中带来了重大挑战。尽管一段时间以来人们已经认识到肿瘤组织龛可能会显著影响癌症干细胞 (CSC)，但关键营养物质（如葡萄糖）在微环境中对影响干细胞样癌细胞及其代谢的作用在很大程度上仍不清楚。在这里，我们报告从人类癌细胞中分离的 SP 细胞表现出比非 SP 细胞更高的糖酵解活性。培养环境中的葡萄糖对 SP 细胞具有深远的影响，这可以证明其能够诱导整体癌细胞群体中 SP 细胞的百分比显著增加，并且葡萄糖饥饿会导致 SP 细胞迅速耗尽。从机制上讲，葡萄糖通过 ATP 介导的 AMPK 抑制和 Akt 途径的激活上调 SP 分数，导致 ATP 依赖性外排泵 ABCG2 的表达升高。重要的是，通过 3-BrOP 抑制糖酵解可显著减少体外 SP 细胞，并损害其在体内形成肿瘤的能力。我们的数据表明，葡萄糖是 Akt 途径介导的 SP 细胞的必需调节剂，靶向糖酵解可能会消除具有潜在显著益处的耐药性 SP 细胞在癌症治疗中。
