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CRIF1 siRNA-Encapsulated PLGA Nanoparticles Suppress Tumor Growth in MCF-7 Human Breast Cancer Cells
Shuyu Piao1, Ikjun Lee1, Seonhee Kim1
1Department of Physiology & Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, 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.
Insights
CRISPR-interacting factor 1 (CRIF1) deficiency impairs mitochondrial function and suppresses breast cancer growth. Silencing CRIF1 reduces oxidative phosphorylation, increases reactive oxygen species, and induces cell cycle arrest, offering a potential anti-cancer therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Mitochondrial oxidative phosphorylation (OXPHOS) is a key target for anti-cancer therapies.
- CR6-interacting factor 1 (CRIF1) is crucial for mitochondrial function and its downregulation impairs cellular respiration.
Purpose of the Study:
- To investigate the anti-cancer effects of CRIF1 deficiency in MCF-7 breast cancer cells and xenograft models.
- To explore the impact of CRIF1 silencing on mitochondrial function and cellular processes.
Main Methods:
- Utilized small interfering RNA (siRNA) and siRNA-encapsulated PLGA nanoparticles to induce CRIF1 deficiency.
- Assessed mitochondrial function, including OXPHOS complex assembly, ROS production, and membrane potential.
- Analyzed cell proliferation, migration, cell cycle progression, and tumor growth in vivo.
Main Results:
- CRIF1 silencing decreased mitochondrial OXPHOS complex I and II assembly, leading to mitochondrial dysfunction.
- Reduced CRIF1 expression elevated reactive oxygen species (ROS) production and induced mitochondrial membrane depolarization and fission.
- CRIF1 inhibition suppressed MCF-7 cell proliferation and migration by inducing G0/G1 cell cycle arrest.
- Intratumoral injection of CRIF1 siRNA nanoparticles inhibited tumor growth and upregulated cell cycle regulators (p53, p21, p16) in mice.
Conclusions:
- CRIF1 deficiency disrupts mitochondrial OXPHOS, impairs mitochondrial function, and elevates ROS levels.
- Targeting CRIF1 demonstrates significant antitumor effects in breast cancer cells and xenografts.
- CRIF1 inhibition represents a promising therapeutic strategy for breast cancer treatment.
