Abstract 4883: Suppression of breast cancer by reprogramming glucose metabolism and energy production with HJC0152

Most mammalian cells use glucose as the primary fuel source. Glucose is metabolized via glycolysis to pyruvate, which is further transferred into mitochondria for generation of ATP through the Krebs cycle in normal condition. However, metabolism is characteristically reprogrammed and cancer cells or highly proliferative cells preferably generate ATP through lactate production by lactate dehydrogenase (LDH/LDHA), referred to as the Warburg effect or metabolic reprogramming toward anaerobic glycolysis. Efficient control of energy metabolism is the key to maintaining metabolic homeostasis, and disturbance in energy balance provokes diseases such as obesity, diabetes and cancer. However, the mechanisms underlying efficient energy metabolic homeostasis and breast cancer development are poorly understood. HJC0152, a novel small-molecule glucose metabolism modulator, was developed using structure-/fragment-based drug design strategies and molecular modeling techniques. Aggressively growing and metastatic breast cancer cells of triple-negative subtype (MDA-MB-231) treated with HJC0152 showed inhibited cell growth. Intriguingly, HJC0152 decreased activity and protein level of LDHA, which resulted in a decrease of lactate production in breast cancer cells. In addition, these cells also exhibited a decrease of glucose uptake by reducing Glut1 and HK2 protein level and modulation of the expression of glycolytic enzymes. Furthermore, HJC0152 treatment causes decreased mitochondrial membrane energy potential, resulting in significantly reduced level of intracellular ATP in MDA-MB-231 cells. Our findings suggest that HJC0152 is capable of reprogramming caner metabolism by modulating glucose metabolism and ATP production. These results may provide a rationale to develop HJC0152 as an effective therapeutics for cancer and other metabolic diseases with aberrant glucose metabolism. In addition, HJC0152 can serve as a molecular probing tool for elucidating the key factors responsible for developing breast cancer and other metabolic diseases. Citation Format: Hyejin Kim, Jiabin Dong, Jimin Xu, Dengfeng Li, Zhi Zheng, Na Ye, Ziwei Zhang, Haiying Chen, Jia Zhou, Qiang Shen. Suppression of breast cancer by reprogramming glucose metabolism and energy production with HJC0152 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4883.