Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma
Year: 2024
Type: article
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.
Source: Drug Resistance Updates
Authors: Yuna Kim, Kwan-Young Jung, Yun Hak Kim, Pan Xu, Baeki E. Kang, Yunju Jo, Navin Pandit, Jeongho Kwon, Karim Gariani, Joanna Gariani, Junguee Lee, Jef Verbeek, Seungyoon Nam, Sung-Jin Bae, Ki-Tae Ha, Hyon-Seung Yi, Minho Shong, Kyun-Hwan Kim, Doyoun Kim, Hee Jung Jung, Chang-Woo Lee, Kwang Rok Kim, Kristina Schoonjans, Johan Auwerx, Dongryeol Ryu
Institutions: Pusan National University, Sungkyunkwan University, Korea Research Institute of Chemical Technology, École Polytechnique Fédérale de Lausanne, Gwangju Institute of Science and Technology, University Hospital of Geneva, Hirslanden Clinique des Grangettes, The Catholic University of Korea Daejeon St. Mary's Hospital, Catholic University of Korea, KU Leuven, Gachon University, Gachon University Gil Medical Center, Kosin University, Chungnam National University
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,420
Funders: National Science Foundation, National Research Foundation, École Polytechnique Fédérale de Lausanne, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Ministry of Trade, Industry and Energy, Ministry of Science, ICT and Future Planning, Ministry of Health and Welfare, Korea Research Institute of Chemical Technology, National Research Foundation of Korea, Korea Drug Development Fund, Ministry of Science and ICT, South Korea, European Research Council, H2020 European Research Council
OpenAlex ID: W4390948824