Rocaglamide reprograms glucose metabolism in erythroleukemic cells via c-MYC transcriptional regulation of TXNIP and HK2

• Published in: Journal of ethnopharmacology 2025-01, Vol.339, p.119145, Article 119145
• Main Authors: Song, Jialei, Liu, Wuling, Xiao, Xiao, Song, Jingrui, Wang, Chunlin, Gajendran, Babu, Wei, Xuenai, Yang, Changfu, Chen, Yunzhi, Yang, Yiying, Huang, Lei, Song, Junrong, Ben-David, Yaacov, Li, Yanmei
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Benzofurans - pharmacology; c-MYC; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Erythroleukemic cell proliferation; Gene Expression Regulation, Neoplastic - drug effects; Glucose - metabolism; Hexokinase - genetics; Hexokinase - metabolism; HK2; Humans; Leukemia, Erythroblastic, Acute - drug therapy; Leukemia, Erythroblastic, Acute - genetics; Leukemia, Erythroblastic, Acute - metabolism; Leukemia, Erythroblastic, Acute - pathology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Rocaglamide; Transcription, Genetic - drug effects; TXNIP
• ISSN: 0378-8741; 1872-7573; 1872-7573
• DOI: 10.1016/j.jep.2024.119145

The theory of traditional Chinese medicine (TCM) views leukemia as an imbalance between cell growth and death mainly caused by blood stasis. Medicinal plants Aglaia Lour. (family Meliaceae) are traditionally used as folk medicine in China. It possesses the effects of removing blood stasis and swelling for treatment of cancer. Rocaglamide (RocA) is the main active phytochemical component of the genus Aglaia Lour. Possessing highly anti-leukemia properties. However, the molecular mechanisms by which RocA exerts its anti-growth effect on erythroleukemia cells are largely unknown. This study aimed to explore the underlying mechanism and glucose metabolism regulation effects of RocA responsible for its anti-erythroleukemia activity. Human erythroleukemic cells were tested for glucose metabolism and treated with glucose deprivation and RocA. MTT assay, cell cycle and apoptosis were used to elucidate growth inhibition. Glucose uptake, glucose consumption and lactate production were evaluated for identification of glucose metabolism. Luciferase assay and ChIP were used to examine the transcriptional activity of c-MYC on the conserved E-boxes binding of the TXNIP (thioredoxin-interacting protein) and HK2 (hexokinase 2) genes. siRNA, shRNA and exogenous transfection were employed to elucidate the effects of TXNIP and HK2 on glucose metabolism. We find that glucose deprivation results in growth inhibition, cell cycle arrest and extensive apoptosis in erythroleukemic cells accompanied by downregulation of c-MYC and HK2, responsible for glucose metabolism. The similar results emerged in RocA treated erythroleukemic cells in presence of glucose. RocA is shown to decrease glucose uptake, glucose consumption and lactate production. Mechanistically, RocA dramatically increases TXNIP expression through interference with c-MYC binding to the promoter of the TXNIP gene. RocA also represses c-MYC transcriptional recognition of conserved E-boxes in the HK2 first intron, resulting in HK2 loss. These results implicate c-MYC as an important regulator of TXNIP and HK2 after RocA treatment. TXNIP overexpression or knockdown of HK2 suppresses the proliferation of erythroleukemic cells. Ectopic TXNIP expression restricts glucose uptake and HK2 suppression decreases glucose utilization. Further, our data suggests that loss of HK2 weakens the RocA-driven inhibition effects. We propose repression of c-MYC or the binding by RocA upregulates TXNIP and downregulates HK2, possibly contribute