Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA.
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.
Cell Death Dis. 2021 Mar 17;12(4):287. doi: 10.1038/s41419-021-03567-1.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selective killing of cancer cells underlines its anticancer potential. However, poor tolerability and resistance underscores the need to identify cancer-selective TRAIL-sensitizing agents. Apigenin, a dietary flavonoid, sensitizes lung cancer cell lines to TRAIL. It remains unknown, however, whether apigenin sensitizes primary lung cancer cells to TRAIL and its underlying mechanisms. Here we show that apigenin reprograms alternative splicing of key TRAIL/death-inducing-signaling-complex (DISC) components: TRAIL Death Receptor 5 (DR5) and cellular-FLICE-inhibitory-protein (c-FLIP) by interacting with the RNA-binding proteins hnRNPA2 and MSI2, resulting in increased DR5 and decreased c-FLIP protein levels, enhancing TRAIL-induced apoptosis of primary lung cancer cells. In addition, apigenin directly bound heat shock protein 70 (Hsp70), promoting TRAIL/DISC assembly and triggering apoptosis. Our findings reveal that apigenin directs alternative splicing and inhibits Hsp70 enhancing TRAIL anticancer activity. These findings underscore impactful synergies between diet and cancer treatments opening new avenues for improved cancer treatments.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）选择性杀伤癌细胞凸显了其抗癌潜力。然而，较差的耐受性和耐药性突出表明需要确定癌症选择性 TRAIL 敏化剂。芹菜素是一种膳食类黄酮，可使肺癌细胞系对 TRAIL 敏感。然而，尚不清楚芹菜素是否使原发性肺癌细胞对 TRAIL 敏感及其潜在机制。在这里，我们发现芹菜素通过与 RNA 结合蛋白 hnRNPA2 和 MSI2 相互作用，重新编程关键的 TRAIL/死亡诱导信号复合物（DISC）成分的选择性剪接：TRAIL 死亡受体 5（DR5）和细胞-FLICE 抑制蛋白（c-FLIP），导致 DR5 水平增加和 c-FLIP 蛋白水平降低，增强 TRAIL 诱导的原发性肺癌细胞凋亡。此外，芹菜素直接结合热休克蛋白 70（Hsp70），促进 TRAIL/DISC 组装并触发细胞凋亡。我们的研究结果表明，芹菜素指导选择性剪接并抑制 Hsp70 增强 TRAIL 的抗癌活性。这些发现强调了饮食与癌症治疗之间的协同作用具有重要意义，为改善癌症治疗开辟了新途径。
