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Splicing reprogramming of TRAIL/DISC-components sensitizes lung cancer cells to TRAIL-mediated apoptosis

Oliver H Voss1,2, Daniel Arango1,3, Justin C Tossey1

  • 1Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA.

Cell Death & Disease
|March 18, 2021
PubMed

Insights

Apigenin, a dietary flavonoid, enhances cancer therapy by sensitizing lung cancer cells to TRAIL-induced apoptosis. It reprograms alternative splicing of key apoptosis regulators and inhibits Hsp70, improving TRAIL

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Drug Discovery

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits anticancer potential but faces challenges with poor tolerability and resistance.
  • Identifying agents that selectively sensitize cancer cells to TRAIL is crucial for improving treatment efficacy.
  • Apigenin, a dietary flavonoid, has shown promise in sensitizing lung cancer cell lines to TRAIL, but its effects on primary cells and mechanisms remain unclear.

Purpose of the Study:

  • To investigate whether apigenin sensitizes primary lung cancer cells to TRAIL-induced apoptosis.
  • To elucidate the underlying molecular mechanisms by which apigenin enhances TRAIL sensitivity.
  • To explore the potential of apigenin as a cancer-selective TRAIL-sensitizing agent.

Main Methods:

  • Apigenin treatment of primary lung cancer cells.
  • Analysis of alternative splicing of TRAIL/death-inducing-signaling-complex (DISC) components, including DR5 and c-FLIP.
  • Investigation of interactions with RNA-binding proteins hnRNPA2 and MSI2.
  • Assessment of apigenin's binding to heat shock protein 70 (Hsp70).
  • Evaluation of TRAIL/DISC assembly and apoptosis induction.

Main Results:

  • Apigenin reprograms alternative splicing of DR5 and c-FLIP by interacting with hnRNPA2 and MSI2.
  • Apigenin treatment leads to increased DR5 and decreased c-FLIP protein levels.
  • Apigenin directly binds Hsp70, promoting TRAIL/DISC assembly and apoptosis.
  • Apigenin enhances TRAIL-induced apoptosis in primary lung cancer cells.

Conclusions:

  • Apigenin sensitizes primary lung cancer cells to TRAIL by modulating alternative splicing and inhibiting Hsp70.
  • Apigenin's mechanisms involve reprogramming RNA splicing of key apoptosis regulators and direct Hsp70 interaction.
  • These findings highlight the synergistic potential of dietary compounds like apigenin in cancer therapy, opening new treatment avenues.

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