DAP3 Is Involved in Modulation of Cellular Radiation Response by RIG-I-Like Receptor Agonist in Human Lung Adenocarcinoma Cells.

Yoshiaki Sato,Eichi Tsuruga,Ikuo Kashiwakura,Hironori Yoshino

doi:10.3390/ijms22010420

Yoshiaki Sato, Eichi Tsuruga + Show 2 more

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https://doi.org/10.3390/ijms22010420

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Abstract

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) mediate anti-viral response through mitochondria. In addition, RLR activation induces anti-tumor effects on various cancers. We previously reported that the RLR agonist Poly(I:C)-HMW/LyoVec™ (Poly(I:C)) enhanced radiosensitivity and that cotreatment with Poly(I:C) and ionizing radiation (IR) more than additively increased cell death in lung adenocarcinoma cells, indicating that Poly(I:C) modulates the cellular radiation response. However, it remains unclear how mitochondria are involved in the modulation of this response. Here, we investigated the involvement of mitochondrial dynamics and mitochondrial ribosome protein death-associated protein 3 (DAP3) in the modulation of cellular radiation response by Poly(I:C) in A549 and H1299 human lung adenocarcinoma cell lines. Western blotting revealed that Poly(I:C) decreased the expression of mitochondrial dynamics-related proteins and DAP3. In addition, siRNA experiments showed that DAP3, and not mitochondrial dynamics, is involved in the resistance of lung adenocarcinoma cells to IR-induced cell death. Finally, we revealed that a more-than-additive effect of cotreatment with Poly(I:C) and IR on increasing cell death was diluted by DAP3-knockdown because of an increase in cell death induced by IR alone. Together, our findings suggest that RLR agonist Poly(I:C) modulates the cellular radiation response of lung adenocarcinoma cells by downregulating DAP3 expression.

Highlights

Mitochondria are essential organelles for regulating cellular functions, such as oxidative phosphorylation, cell death, and immune responses [1,2]
Mitochondria are highly dynamic organelles that undergo fusion and fission, referred to as mitochondrial dynamics [3]. These processes are regulated by several proteins [3], e.g., mitochondrial fusion is mainly regulated by mitofusin-1/2 (Mfn1/2) and optic atrophy protein 1 (OPA1), with the former involved in outer membrane fusion and the latter in inner membrane fusion, whereas dynamin-related protein 1 (Drp1) is the main protein that initiates mitochondrial fission
We investigated the relationship between mitochondrial dynamics, death-associated protein 3 (DAP3), and the modulation of the cellular radiation response by Poly(I:C) in human lung adenocarcinoma cells

Summary

Introduction

Mitochondria are essential organelles for regulating cellular functions, such as oxidative phosphorylation, cell death, and immune responses [1,2]. Mitochondria are highly dynamic organelles that undergo fusion and fission, referred to as mitochondrial dynamics [3]. These processes are regulated by several proteins [3], e.g., mitochondrial fusion is mainly regulated by mitofusin-1/2 (Mfn1/2) and optic atrophy protein 1 (OPA1), with the former involved in outer membrane fusion and the latter in inner membrane fusion, whereas dynamin-related protein 1 (Drp1) is the main protein that initiates mitochondrial fission. The mitochondria contain their own DNA and ribosomes that synthesize mitochondrial DNA (mtDNA)-encoded proteins [4]. These characteristics have been reported to be important in self-maintenance of mitochondrial functions in response to various stress conditions such as viral infection [5,6,7].

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