Zhang Wenbo, Xu Ying, Xu Qinggang, Shi Haifeng, Shi Juanjuan, Hou Yongzhong
Department of General Surgery, The Affiliated People's Hospital, Jiangsu University, Zhen Jiang, Jiangsu 212002, People's Republic of China.
Institute of Life Science, Jiangsu University, Zhenjiang, Jiangsu Province 212002, People's Republic of China.
Carcinogenesis. 2017 Jul 1;38(7):748-755. doi: 10.1093/carcin/bgx035.
Malignant cancer cell uncontrolled growth depends on the persistent nutrient availability such as glucose and amino acids, which is required for cancer cell energetic and biosynthetic pathways. As a nuclear hormone receptor, peroxisome-proliferator-activated receptor δ (PPARδ) plays a critical role in inflammation and cancer, however, it is still unclear the regulatory mechanism of PPARδ on cancer cell metabolism. Here, we found that PPARδ directly regulated neutral amino acid transporter SLC1-A5 (solute carrier family 1 member 5) and glucose transporter-1 (Glut1) gene transcription, leading to uptake of glucose and amino acid, activation of mTOR signaling, and tumor progression. In contrast, silence of PPARδ or its antagonist inhibited this event. More importantly, PPARδ promoted cancer cell metabolic reprogramming resulting in chemoresistance, which was alleviated by PPARδ antagonist. These findings revealed a novel mechanism of PPARδ-mediated tumor progression, which provided a potential strategy for cancer treatment.
恶性癌细胞的不受控制的生长依赖于持续的营养物质供应，如葡萄糖和氨基酸，这是癌细胞能量和生物合成途径所必需的。作为一种核激素受体，过氧化物酶体增殖物激活受体δ（PPARδ）在炎症和癌症中起关键作用，然而，PPARδ对癌细胞代谢的调节机制仍不清楚。在这里，我们发现PPARδ直接调节中性氨基酸转运体SLC1 - A5（溶质载体家族1成员5）和葡萄糖转运蛋白-1（Glut1）的基因转录，导致葡萄糖和氨基酸的摄取、mTOR信号的激活以及肿瘤进展。相反，PPARδ的沉默或其拮抗剂抑制了这一过程。更重要的是，PPARδ促进癌细胞代谢重编程，导致化疗耐药，而PPARδ拮抗剂可减轻这种耐药性。这些发现揭示了PPARδ介导肿瘤进展的新机制，为癌症治疗提供了潜在策略。
