Abstract:
The HER2-positive subtype accounts for approximately one-fifth of all breast cancers. Insensitivity and development of acquired resistance to targeted therapies in some patients contribute to their poor prognosis. HER2 overexpression is associated with metabolic reprogramming, facilitating cancer cell growth and survival. Novel liver X receptor (LXR) ligand GAC0001E5 (1E5) has been shown to inhibit cancer cell proliferation by disrupting glutaminolysis and inducing oxidative stress. In this study, HER2-positive breast cancer cells were treated with 1E5 to determine their potential inhibitory effects and mechanisms of action in HER2-positive breast cancers. Similar to previous observations in other cancer types, 1E5 treatments inhibited LXR activity, expression, and cancer cell proliferation. Expression of fatty acid synthesis genes, including fatty acid synthase (FASN), was downregulated following 1E5 treatment, and results from co-treatment experiments with an FASN inhibitor suggest that the same pathway is targeted by 1E5. Treatments with 1E5 disrupted glutaminolysis and resulted in increased oxidative stress. Strikingly, HER2 transcript and protein levels were both significantly downregulated by 1E5. Taken together, these findings indicate the therapeutic potential of targeting HER2 overexpression and associated metabolic reprogramming via the modulation of LXR in HER2-positive breast cancers.
摘要:
HER2阳性亚型约占所有乳腺癌的五分之一。一些患者对靶向治疗的不敏感和获得性耐药性的发展导致其预后不良。HER2过表达与代谢重编程相关,促进癌细胞生长和存活。新型肝X受体(LXR)配体GAC0001E5(1E5)已显示通过破坏谷氨酰胺分解和诱导氧化应激来抑制癌细胞增殖。在这项研究中,用1E5处理HER2阳性乳腺癌细胞以确定其在HER2阳性乳腺癌中的潜在抑制作用和作用机制。与以前在其他癌症类型中的观察结果相似,1E5处理抑制LXR活性,表达式,和癌细胞增殖。脂肪酸合成基因的表达,包括脂肪酸合成酶(FASN),在1E5治疗后下调,与FASN抑制剂共同处理实验的结果提示1E5靶向相同的途径。用1E5处理破坏了谷氨酰胺分解并导致氧化应激增加。引人注目的是,HER2转录物和蛋白质水平均被1E5显著下调。一起来看,这些研究结果表明,在HER2阳性乳腺癌中,通过调节LXR靶向HER2过表达和相关的代谢重编程具有治疗潜力.