Abstract
Non-small cell lung cancer is the most common type of lung cancer, accounting for more than 80% of this tumor. Ubiquitin-specific protease (USP) 14 is one of the 100 deubiquitinating enzymes that is overexpressed in lung cancer and has been validated as a therapeutic target. The aim of this study is to determine whether the accumulation of ubiquitinated proteins results in endoplasmic reticulum (ER) stress-mediated autophagy. To inhibit USP-14, A549 lung cancer cells were treated with USP-14 siRNA and IU1-47 (20 μM). The protein level, mRNA expression, and cell cycle analysis were evaluated using Western blot, real-time PCR, and flow cytometry, respectively. We found that treating A549 cells with USP14 inhibitors significantly reduced the proliferation rate and induced cell cycle arrest at G2/M phase. We also found that USP14 inhibitors did not induce apoptosis but actually induced autophagy through accumulation of ubiquitinated proteins/ER stress/unfolded protein response (UPR) axis. Moreover, we have for the first time demonstrated that the USP14 inhibition induces ER stress–mediated autophagy in A549 cells by activation of c-Jun N-terminal kinase 1 (JNK1). In conclusion, the current investigation represents a new mechanism by which inhibition of USP14 triggers autophagy via ER stress–mediated UPR in A549 cells.
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This study was funded by the grant obtained from the Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran (grant no.: 60424).
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Moghadami, AA., Aboutalebi Vand Beilankouhi, E., Kalantary-Charvadeh, A. et al. Inhibition of USP14 induces ER stress–mediated autophagy without apoptosis in lung cancer cell line A549. Cell Stress and Chaperones 25, 909–917 (2020). https://doi.org/10.1007/s12192-020-01125-w
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DOI: https://doi.org/10.1007/s12192-020-01125-w