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

Oliver H Voss; Daniel Arango; Justin C Tossey; Miguel A Villalona Calero; Andrea I Doseff

doi:10.1038/s41419-021-03567-1

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

Cell Death Dis. 2021 Mar 17;12(4):287. doi: 10.1038/s41419-021-03567-1.

Authors

Oliver H Voss^#^{1

2}, Daniel Arango^#^{1

3}, Justin C Tossey¹, Miguel A Villalona Calero⁴, Andrea I Doseff⁵

Affiliations

¹ Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA.
² Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.
³ Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD, USA.
⁴ Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.
⁵ Department of Physiology and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA. doseffan@msu.edu.

^# Contributed equally.

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-FLIP_S 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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Apoptosis
Cell Line, Tumor
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Signal Transduction
TNF-Related Apoptosis-Inducing Ligand / metabolism*

Substances

TNF-Related Apoptosis-Inducing Ligand