CRIF1 siRNA-Encapsulated PLGA Nanoparticles Suppress Tumor Growth in MCF-7 Human Breast Cancer Cells
-
Published:2023-04-18
Issue:8
Volume:24
Page:7453
-
ISSN:1422-0067
-
Container-title:International Journal of Molecular Sciences
-
language:en
-
Short-container-title:IJMS
Author:
Piao Shuyu1ORCID, Lee Ikjun1, Kim Seonhee1, Park Hyewon2, Nagar Harsha1, Choi Su-Jeong1, Vu Giang-Huong1, Kim Minsoo1, Lee Eun-Ok1, Jeon Byeong-Hwa1ORCID, Kim Dong Woon2ORCID, Seo Youngduk3ORCID, Kim Cuk-Seong1ORCID
Affiliation:
1. Department of Physiology & Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea 2. Department of Anatomy and Cell Biology & Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea 3. Department of Nuclear Medicine, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea
Abstract
Mitochondrial oxidative phosphorylation (OXPHOS) system dysfunction in cancer cells has been exploited as a target for anti-cancer therapeutic intervention. The downregulation of CR6-interacting factor 1 (CRIF1), an essential mito-ribosomal factor, can impair mitochondrial function in various cell types. In this study, we investigated whether CRIF1 deficiency induced by siRNA and siRNA nanoparticles could suppress MCF-7 breast cancer growth and tumor development, respectively. Our results showed that CRIF1 silencing decreased the assembly of mitochondrial OXPHOS complexes I and II, which induced mitochondrial dysfunction, mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential depolarization, and excessive mitochondrial fission. CRIF1 inhibition reduced p53-induced glycolysis and apoptosis regulator (TIGAR) expression, as well as NADPH synthesis, leading to additional increases in ROS production. The downregulation of CRIF1 suppressed cell proliferation and inhibited cell migration through the induction of G0/G1 phase cell cycle arrest in MCF-7 breast cancer cells. Similarly, the intratumoral injection of CRIF1 siRNA-encapsulated PLGA nanoparticles inhibited tumor growth, downregulated the assembly of mitochondrial OXPHOS complexes I and II, and induced the expression of cell cycle protein markers (p53, p21, and p16) in MCF-7 xenograft mice. Thus, the inhibition of mitochondrial OXPHOS protein synthesis through CRIF1 deletion destroyed mitochondrial function, leading to elevated ROS levels and inducing antitumor effects in MCF-7 cells.
Funder
Basic Science Research Program through the National Research Foundation of Korea Ministry of Education Chungnam National University
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference34 articles.
1. The Warburg Effect: How Does it Benefit Cancer Cells?;Liberti;Trends Biochem. Sci.,2016 2. The reverse Warburg effect is likely to be an Achilles’ heel of cancer that can be exploited for cancer therapy;Fu;Oncotarget,2017 3. Oxidative Phosphorylation as an Emerging Target in Cancer Therapy;Ashton;Clin. Cancer Res.,2018 4. Nayak, A.P., Kapur, A., Barroilhet, L., and Patankar, M.S. (2018). Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer. Cancers, 10. 5. An inhibitor of oxidative phosphorylation exploits cancer vulnerability;Molina;Nat. Med.,2018
|
|