Abstract 2418: JQ-1, a novel c-Myc inhibitor, suppressed cell proliferation and metabolism through the downregulation of lactate dehydrogenase A in ovarian cancer cells.

Abstract

Abstract Introduction: Amplification and overexpression of c-Myc is very common in human cancers, including ovarian cancer. Heightened aerobic glycolysis (the Warburg effect) is a key metabolic hallmark of cancer and is thought to be under the control of c-Myc. JQ-1 is a selective small-molecure BET bromodomain inhibitor, and BET inhibition by JQ-1 leads to the downregulation of MYC transcription. Thus, JQ-1 functions as a novel c-Myc inhibitor and has been found to potently suppress tumor growth in hematologic malignancies. Thus, we aim to assess the impact of JQ-1 on the proliferation of human ovarian cancer cell lines and further explore its effects on cellular metabolism, especially the aerobic glycolysis pathway and its key enzyme—lactate dehydrogenase A (LDHA). Methods: Three human ovarian cancer cell lines (HEY and SKOV3) were used in this study. Cell proliferation was assessed by MTT assay after exposure to JQ-1 (generously provided by the laboratory of Dr. James E. Bradner). Cell cycle progression was evaluated by Cellometer. Apoptosis was assessed by Annexin V-FITC assay. Expression of c-Myc, p21, phosphorylated-LDHA and pan-LDHA were detected by Western blot analysis. Cellular glucose uptake, ATP production, reactive oxygen species (ROS), LDHA activity and lactate production were determined by ELISA assay using the corresponding commercial kits. Mitochondrial membrane potential changes were measured by JC-1 staining via Cellometer. Results: JQ-1 suppressed cellular proliferation (IC50 = 360 nM for HEY, p = 0.00001; IC50 = 3500 nM for SKOV3, p = 0.0007) via G1 cell cycle arrest in the ovarian cancer cell lines, but only caused moderate apoptosis. Western blot analysis demonstrated that JQ-1 increased p21 expression and decreased expression of c-Myc and phosphorylation of LDHA. In parallel, treatment with JQ-1 decreased LDHA activity, glucose uptake, mitochondrial membrane potential, lactate and ATP production and increased ROS levels in the ovarian cancer cell lines. Conclusions: We find that targeting c-Myc by JQ-1 significantly suppresses proliferation through G1 arrest in ovarian cancer cell lines. In addition, JQ-1 had multiple influences on cancer metabolism, particularly in the aerobic glycolysis pathway. JQ-1 reduced both the expression and activity of LDHA, inhibited lactate production and decreased the energy supply of the ovarian cancer cells. This evidence suggests that JQ-1 may be a promising targeted therapy for ovarian cancer through its effects on both cell proliferation and metabolism. Citation Format: Haifeng Qiu, Chunxiao Zhou, Amanda L. Jackson, Joshua E. Kilgore, Victoria L. Bae-Jump. JQ-1, a novel c-Myc inhibitor, suppressed cell proliferation and metabolism through the downregulation of lactate dehydrogenase A in ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2418. doi:10.1158/1538-7445.AM2013-2418