No 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.

Lack of targeted strategies for preventing and treating estrogen receptor (ER)-negative breast cancer (ENBC) is an unmet clinical challenge. ENBCs including triple-negative BCs (TNBC) constitute 30-40% of BC cases and are prone to develop remote metastasis and local recurrence, resulting in the majority of deaths in BC patients. Dysregulated glucose and energy metabolism is critically involved in the development and progression of various cancers via promoting aberrant cell growth, malignant transformation and metastasis. Nevertheless, the potential role of glucose/energy metabolism in ENBC carcinogenesis has sparsely been explored, thus representing a key knowledge gap and a potential avenue for effective targeted therapies. Despite a substantial amount of effort has been made towards anticancer metabolic and biogenetic medications, none has progressed into clinical use, due to their limited potency, specificity or drug properties such as toxicity and poor bioavailability. We recently developed HJC0152, a novel small molecule anticancer agent, using structure- and fragment-based drug design strategies and molecular modeling techniques in our initial attempt to develop non-peptide STAT3 inhibitors for anticancer use. HJC0152 significantly inhibits proliferation of BC cells, induces apoptosis, reduces ER-negative mammary tumor development, suppresses ENBC xenograft tumor growth, and blocks lung metastasis in vivo. Intriguingly, HJC0152 differentially modulates expression of glycolytic enzymes including HK1, PFK-L, PFKFB2, ENO2, PDH, PDK1, PGAM1 and ALDOA in a time-dependent manner. HJC0152 also regulates the transcription of genes involved in glucose and mitochondrial energy metabolism, including the subunits of mitochondrial respiratory chain complexes. Functional assessments further demonstrate that HJC0152 significantly modulates respiratory chain complex function. Via in silico and Unique Polymer Technology (UPT) strategy, we identified a number of putative HJC0152-interacting targets for validation studies. Our findings suggest that HJC0152 is capable of reprogramming/restoring the dysregulated glucose metabolism by inducing specific glycolytic enzyme expression and mitochondrial respiratory chain function, likely via targeting upstream key signal molecule(s) that regulates glucose and energy metabolism, thereby suppressing breast cancer development and progression to metastasis. 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: Dong J, Kim H, Xu J, Li D, Zhang Z, Zheng Z, Ye N, Chen H, Zhou J, Shen Q. Suppression of breast carcinogenesis and metastasis by targeting glucose metabolism with HJC0152 [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 P5-21-19.