Inhibition of TRF2 Leads to Ferroptosis, Autophagic Death, and Apoptosis by Causing Telomere Dysfunction

Abstract

Background. Gastric cancer (GC) is an aggressive malignancy with a high mortality rate and poor prognosis. Telomeric repeat-binding factor 2 (TRF2) is a critical telomere protection protein. Emerging evidence indicates that TRF2 may be an essential treatment option for GC; however, the exact mechanism remains largely unknown. Objective. We aimed to explore the role of TRF2 in GC cells. The function and molecular mechanisms of TRF2 in the pathogenesis of GC were mainly discussed in this study. Methods. Relevant data from GEPIA and TCGA databases regarding TRF2 gene expression and its prognostic significance in GC samples were analyzed. Analysis of 53BP1 foci at telomeres by immunofluorescence, metaphase spreads, and telomere-specific FISH analysis was carried out to explore telomere damage and dysfunction after TRF2 depletion. CCK8 cell proliferation, trypan blue staining, and colony formation assay were performed to evaluate cell survival. Apoptosis and cell migration were determined with flow cytometry and scratch-wound healing assay, respectively. qRT-PCR and Western blotting were carried out to analyze the mRNA and protein expression levels after TRF2 depletion on apoptosis, autophagic death, and ferroptosis. Results. By searching with GEPIA and TCGA databases, the results showed that the expression levels of TRF2 were obviously elevated in the samples of GC patients, which was associated with adverse prognosis. Knockdown of TRF2 suppressed the cell growth, proliferation, and migration in GC cells, causing significant telomere dysfunction. Apoptosis, autophagic death, and ferroptosis were also triggered in this process. The pretreatment of chloroquine (autophagy inhibitor) and ferrostatin-1 (ferroptosis inhibitor) improved the survival phenotypes of GC cells. Conclusion. Our data suggest that TRF2 depletion can inhibit cell growth, proliferation, and migration through the combined action of ferroptosis, autophagic death, and apoptosis in GC cells. The results indicate that TRF2 might be used as a potential target to develop therapeutic strategies for treating GC.

Ferroptosis and its role in gastric and colorectal cancers

“…Knockdown of TRF2 led to decreased expression of SLC7A11 and GPX4, resulting in ferroptosis in GC cells. In addition, TRF2 deletion also inhibited GC cell growth and proliferation by inducing autophagy and apoptosis in tumor cells together [ 106 ]. MET metabolism plays an important role in the regulation of ferroptosis.…”

miR-29b-1-5p exacerbates myocardial injury induced by sepsis in a mouse model by targeting TERF2

“…Lachettini et al [58] reported that TERF2 knockdown induces autophagy by sequestering HMGB1 into the nucleus, where it exerts its pro-autophagic effect when it is shuttled from the nucleus to the cytosol [59]. Moreover, inhibition of TERF2 leads to autophagic death, and apoptosis has also been proven to occur in gastric cancer [60]. Most current studies suggested that the induction of autophagy in sepsis can ameliorate sepsis-induced myocardial damage [30,61].…”