Abstract
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-FLIPS 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.
Highlights
Lung cancer remains the deadliest of all cancers, and non-small cell lung carcinoma (NSCLC) accounts for 85% of all lung cancer deaths[1,2]
Of the DISC proteins examined, we found that apigenin pretreatment followed by Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) altered only death receptor 5 (DR5), c-FLIPS, and caspase-8, while c-FLIPL, Fas-Associated Death Domain (FADD), and Hsp[70] remained at levels comparable to those found in cells treated with DMSO in both A549 and Calu-1 cells (Fig. 2)
We found that in the absence of apigenin, DR5 associated with Hsp[70] efficiently, but DR5 binding to FADD and caspase-8 was almost undetectable (Figs. 5a and S6a)
Summary
Lung cancer remains the deadliest of all cancers, and non-small cell lung carcinoma (NSCLC) accounts for 85% of all lung cancer deaths[1,2]. NSCLC is highly resistant to therapy and shows a dismal 5-year survival rate of only 19%, underscoring the need to identify novel anticancer strategies[2,3,4]. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a proapoptotic ligand that has attracted great interest because of its capacity to induce apoptosis selectively of cancer cells[5,6,7]. Emerging new TRAIL with higher agonistic capacity and reduced systemic toxicity[11], prompted interest to identify sensitizers to cancer-selective TRAIL therapy contributing to overcome resistance[12]
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