Department of Biosciences, Jamia Millia Islamia (A Central University), New Delhi, 110025, India.
Medical Biotechnology Laboratory, Dr B R Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, India.
Sci Rep. 2024 Oct 4;14(1):23147. doi: 10.1038/s41598-024-72221-5.
Reprogrammed glucose metabolism is considered as the hallmark of cancer with therapeutic implications. Phytocompounds have potential to inhibit cancer metabolism. Here, we tested the ability of Withaferin A (WA), a withanolide derived from Withania somnifera, in modulating cancer metabolism. The assessed effect of WA on aerobic glycolysis in breast cancer cell lines showed that WA decreases the glucose uptake, lactate production and ATP generation by inhibiting the expression of key glycolytic enzymes i.e., GLUT1, HK2 and PKM2. We also identified that WA induced inhibition of cancer glycolysis by targeting c-myc as validated by silencing experiments followed by metabolic readouts. Decreased glycolysis resulted in reduced cell viability, biomass and colony forming ability of breast cancer cells. To further validate our in vitro findings in breast cancer patients, we analyzed 90 metabolic pathways in ~ 2000 breast tumors and observed that glycolysis is the most deregulated pathway in breast tumors. Deregulated glycolysis also predicted poor prognosis in breast cancer patients. In addition, patient data showed correlation between c-myc expression and glycolytic deregulation in breast cancer. Taken together, our results highlight the role of WA in inhibiting breast cancer metabolism via c-myc/glycolysis axis.
重新编程的葡萄糖代谢被认为是癌症的标志，具有治疗意义。植物化合物具有抑制癌症代谢的潜力。在这里，我们测试了从印度人参中提取的 Withaferin A (WA) 抑制癌症代谢的能力。WA 对乳腺癌细胞系有氧糖酵解的评估作用表明，WA 通过抑制关键糖酵解酶即 GLUT1、HK2 和 PKM2 的表达，降低葡萄糖摄取、乳酸生成和 ATP 生成。我们还通过沉默实验和代谢读数鉴定出 WA 通过靶向 c-myc 诱导癌症糖酵解抑制。糖酵解减少导致乳腺癌细胞活力、生物量和集落形成能力降低。为了进一步验证我们在乳腺癌患者中的体外发现，我们分析了 2000 多个乳腺癌肿瘤中的 90 种代谢途径，发现糖酵解是乳腺癌中最失调的途径。糖酵解失调也预示着乳腺癌患者预后不良。此外，患者数据显示 c-myc 表达与乳腺癌中的糖酵解失调之间存在相关性。总之，我们的研究结果强调了 WA 通过 c-myc/糖酵解轴抑制乳腺癌代谢的作用。
