Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma
- Authors
- Kim, Yuna; Jung, Kwan-Young; Kim, Yun Hak; Xu, Pan; Kang, Baeki E.; Jo, Yunju; Pandit, Navin; Kwon, Jeongho; Gariani, Karim; Gariani, Joanna; Lee, Junguee; Verbeek, Jef; Nam, Seungyoon; Bae, Sung-Jin; Ha, Ki-Tae; Yi, Hyon-Seung; Shong, Minho; Kim, Kyun-Hwan; Kim, Doyoun; Jung, Hee Jung; Lee, Chang-Woo; Kim, Kwang Rok; Schoonjans, Kristina; Auwerx, Johan; Ryu, Dongryeol
- Issue Date
- Mar-2024
- Publisher
- CHURCHILL LIVINGSTONE
- Keywords
- DDX3X; ERK1/2 phosphorylation; Hepatocellular carcinoma; SIRT7 inhibitor; Sorafenib resistance
- Citation
- Drug Resistance Updates, v.73
- Journal Title
- Drug Resistance Updates
- Volume
- 73
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/91482
- DOI
- 10.1016/j.drup.2024.101054
- ISSN
- 1368-7646
1532-2084
- Abstract
- Aims: Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance. Methods: Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib. Results: SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1β inhibition. Conclusions: SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling. © 2024 The Authors
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