Abstract P1-02-08: Reprogramming glucose metabolism and energy production in breast cancer cells

Abstract

Abstract Most mammalian cells use glucose as a main fuel source. Glucose is metabolized via glycolysis to pyruvate, which enters the mitochondria and then generates ATP through 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 aerobic 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- and 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 decreased activity and protein level of LDHA, which resulted in a decrease lactate production. In addition, these cells also exhibited decreased glucose uptake and HK2 protein level. Furthermore, the amount of intracellular ATP in MDA-MB-231 cells was significantly reduced. 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 therapeutic 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.This work was supported by Grants P50 CA097007, and P30DA028821 (JZ) from the NIH, CPRIT (JZ), John Sealy Memorial Endowment Fund (JZ), DFI Grants from MD Anderson Cancer Center (QS), Holden Family Research Grant in BC Prevention (QS), and NCI PREVENT Program HHSN26100002 (QS). Citation Format: Kim H, Dong J, Xu J, Li D, Zheng Z, Ye N, Zhang Z, Chen H, Zhou J, Shen Q. Reprogramming glucose metabolism and energy production in breast cancer cells [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-02-08.