Inhibition of Uncoupling Protein 2 Enhances the Radiosensitivity of Cervical Cancer Cells by Promoting the Production of Reactive Oxygen Species

Abstract

Objective. The mechanism of enhanced radiosensitivity induced by mitochondrial uncoupling protein UCP2 was investigated in HeLa cells to provide a theoretical basis as a novel target for cervical cancer treatment. Methods. HeLa cells were irradiated with 4 Gy X-radiation at 1.0 Gy/min. The expression of UCP2 mRNA and protein was assayed by real-time quantitative polymerase chain reaction and western blotting. UCP2 siRNA and negative control siRNA fragments were constructed and transfected into HeLa cells 24 h after irradiation. The effect of UCP2 silencing and irradiation on HeLa cells was determined by colony formation, CCK-8 cell viability, γH2AX immunofluorescence assay of DNA damage, Annexin V-FITC/PI apoptosis assay, and propidium iodide cell cycle assay. The effects on mitochondrial structure and function were investigated with fluorescent probes including dichlorodihydrofluorescein diacetate (DCFH-DA) assay of reactive oxygen species (ROS), rhodamine 123, and MitoTracker Green assay of mitochondrial structure and function. Results. Irradiation upregulated UCP2 expression, and UCP2 knockdown decreased the survival of irradiated HeLa cells. UCP2 silencing sensitized HeLa cells to irradiation-induced DNA damage and led to increased apoptosis, cell cycle arrest in G2/M, and increased mitochondrial ROS. Increased radiosensitivity was associated with an activation of P53, decreased Bcl-2, Bcl-xl, cyclin B, CDC2, Ku70, and Rad51 expression, and increased Apaf-1, cytochrome c, caspase-3, and caspase-9 expression. Conclusions. UCP2 inhibition augmented the radiosensitivity of cervical cancer cells, and it may be a potential target of radiotherapy of advanced cervical cancer.

Prediction of Response to Radiotherapy by Characterizing the Transcriptomic Features in Clinical Tumor Samples across 15 Cancer Types

“…Genes involved in migration, cell proliferation, cell invasion, tumor metastasis, and EMT were significantly upregulated in the PD group (e.g., MDC1, UCP2, RBM45, BCL9L, P2RX6, RER1, EFNA2, CASK, CERCAM, and PTPRN). Interestingly, MDC1 has been reported as a key regulator of the DNA damage response in higher eukaryotes [ 26 ], and UCP2 and RBM45 have been implicated in RT resistance [ 27 , 28 ]. Among the top 100 genes, there was a class of genes related to a ubiquitination proteasome hydrolysis system, such as RBM45, TRIM9, PTPRN, RNF123, RNF220, and DTX1.…”

“…In this study, we identified the differentially expressed genes between RT responder and nonresponder. Among them, MDC1 [ 26 ], UCP2 [ 27 ], and RBM45 [ 28 ] have been demonstrated to be involved in the DNA damage pathway and radiosensitivity. MDC1 [ 26 ] was identified as a component of DNA repair complex, controlling the damage-induced cell cycle arrest checkpoint.…”

UCP1 modulates immune infiltration level and survival outcome in ovarian cancer patients

“…Recent studies have shown that UCPs are involved in tumor progression, remodeling tumor microenvironment [ 7 ], chemoresistance [ 23 ] and survival of cancer patients [ 24 ]. Given the functional significance of UCPs in cancer, several studies suggested that UCPs might be a reliable marker for predicting prognoses of tumor patients.…”

UCP1 modulates Immune Infiltration Level and Survival Outcome in Ovarian Cancer Patients

“…Recent studies have shown that UCPs are involved in tumor progression, remodeling tumor microenvironment [23], chemoresistance [24] and survival of cancer patients [25]. Given the functional signi cance of UCPs in cancer, several studies suggested that UCPs might be a reliable marker for predicting prognoses of tumor patients.…”