IFN-\u03b3 restores the impaired function of RNase L and induces mitochondria-mediated apoptosis in lung cancer

Huijing Yin,Zhengyu Jiang,Ping Zhang,Shuoer Wang

doi:10.1038/s41419-019-1902-9

Abstract

RNase L is an essential component in interferon (IFN)-mediated antiviral signaling that showed antitumor effects in cancer. Cancer immunotherapy based on interferon has achieved encouraging results that indicate an applicable potential for cancer therapy. Here we showed that function of RNase L, though highly upregulated, was functionally impaired both in nuclear and cytoplasm in lung cancer cells. In normal lung epithelial cells, RNase L activation induced by 2–5A promoted nuclear condensation, DNA cleavage, and cell apoptosis, while in lung cancer cells, these processes were inhibited and RNase L-mediated downregulation of fibrillarin, Topo I and hnRNP A1 was also impaired in lung cancer cells. Moreover, the impairment of RNase L in lung cancer cells was due to the elevated expression of RLI. Application of IFN-γ to lung cancer cells led to enhanced expression of RNase L that compensated the RLI inhibition and restored the cytoplasmic and nuclear function of RNase L, leading to apoptosis of lung cancer cells. Thus, the present study discovered the impaired function and mechanism of RNase L in lung cancer cells and proved the efficacy of IFN-γ in restoring RNase L function and inducing apoptosis in the lung cancer cell. These results indicated the RNase L as a therapeutic target in lung cancer cells and immunotherapy of IFN-γ may serve as an adjuvant to enhance the efficacy.

Highlights

Research and treatment for lung cancer have focused more on the altered intrinsic mechanism that results in tumorigenesis[1,2]
RNase L was highly elevated in all lung cancer cell lines but not in breast cancer cell line (Fig. 1a)
We further measured the expression in specific fractions, respectively, and found that RNase L was elevated in lung cancer cells (Fig. 1b) in cytoplasm (Fig. 1c) and in nucleus (Fig. 1d), indicating the different function of RNase L in lung cancer cells

Summary

Introduction

Research and treatment for lung cancer have focused more on the altered intrinsic mechanism that results in tumorigenesis[1,2]. Intracellular double-stranded RNA activated OAS and synthesized 2–5A from ATP The latter further activates RNase L as endoribonuclease to catalyze single-stranded RNA (ssRNA) or rRNA, inhibiting virus replication and inducing cell apoptosis[6,7,8,9,10]. The broader function of RNase L has been identified in regulating RNA metabolism, proliferation, apoptosis, differentiation, and autophagy[3,11,12] These functions are achieved through the cleavage of rRNA or regulate protein translation through translational termination or direct mRNA catalyzation by RNase L3,13–15. Based on these regulatory mechanisms, RNase L is identified as an antitumor effector, which inhibits c-Myc expression

Methods

Results

Conclusion