Essential roles of exosome and circRNA_101093 on ferroptosis desensitization in lung adenocarcinoma

Abstract

Background Resistance to ferroptosis, a regulated cell death caused by iron‐dependent excessive accumulation of lipid peroxides, has recently been linked to lung adenocarcinoma (LUAD). Intracellular antioxidant systems are required for protection against ferroptosis. The purpose of the present study was to investigate whether and how extracellular system desensitizes LUAD cells to ferroptosis. Methods Established human lung fibroblasts MRC‐5, WI38, and human LUAD H1650, PC9, H1975, H358, A549, and H1299 cell lines, tumor and matched normal adjacent tissues of LUAD, and plasma from healthy individuals and LUAD patients were used in this study. Immunohistochemistry and immunoblotting were used to analyze protein expression, and quantitative reverse transcription‐PCR was used to analyze mRNA expression. Cell viability, cell death, and the lipid reactive oxygen species generation were measured to evaluate the responses to ferroptosis. Exosomes were observed using transmission electron microscope. The localization of arachidonic acid (AA) was detected using click chemistry labeling followed by confocal microscopy. Interactions between RNAs and proteins were detected using RNA pull‐down, RNA immunoprecipitation and photoactivatable ribonucleoside‐enhanced crosslinking and immunoprecipitation methods. Proteomic analysis was used to investigate RNA‐regulated proteins, and metabolomic analysis was performed to analyze metabolites. Cell‐derived xenograft, patient‐derived xenograft, cell‐implanted intrapulmonary LUAD mouse models and plasma/tissue specimens from LUAD patients were used to validate the molecular mechanism. Results Plasma exosome from LUAD patients specifically reduced lipid peroxidation and desensitized LUAD cells to ferroptosis. A potential explanation is that exosomal circRNA_101093 (cir93) maintained an elevation in intracellular cir93 in LUAD to modulate AA, a poly‐unsaturated fatty acid critical for ferroptosis‐associated increased peroxidation in the plasma membrane. Mechanistically, cir93 interacted with and increased fatty acid‐binding protein 3 (FABP3), which transported AA and facilitated its reaction with taurine. Thus, global AA was reduced, whereas N‐arachidonoyl taurine (NAT, the product of AA and taurine) was induced. Notably, the role of NAT in suppressing AA incorporation into the plasma membrane was also revealed. In pre‐clinical in vivo models, reducing exosome improved ferroptosis‐based treatment. Conclusion Exosome and cir93 are essential for desensitizing LUAD cells to ferroptosis, and blocking exosome may be helpful for future LUAD treatment.

circ_0052184 Promotes Colorectal Cancer Progression via Targeting miR-604/HOXA9 Axis

“…circ_0014130 acted as a molecular sponge for miR-197-3p and participated in the drug sensitivity and development of colorectal cancer by regulating the miR-197-3p/PFKFB3 axis [ 20 ]. Downregulation of circ_0011385 in colorectal cancer inhibited cell proliferation and promoted apoptosis by regulating the miR-330-3p/MYO6 axis [ 21 ]. circ_0001666 can inhibit the progression of colorectal cancer by regulating the miR-576-5p/PCDH10 axis [ 22 ].…”

circ_0052184 promotes colorectal cancer progression via targeting miR-604/HOXA9 axis

“…circ_0014130 acted as a molecular sponge for miR-197-3p and participate in the drug sensitivity and development of colorectal cancer by regulating the miR-197-3p/PFKFB3 axis [20]. Downregulation of circ_0011385 in colorectal cancer inhibited cell proliferation, and promoted apoptosis by regulating the miR-330-3p/MYO6 axis [21]. Circ_0001666 can inhibit the progression of colorectal cancer by regulating the miR-576-5p/PCDH10 axis [22].…”

Non-Coding Ribonucleic Acids as Regulators of Ferroptosis in Cancer

“…Circ_0067934 silence could raise the level of iron and ROS in cells [160] . Recently, exosome circRNA_101093 could interact with Fatty Acid-Binding Protein 3 (FABP3) and increase the reaction of arachidonic acid with taurine, which was critical for desensitization of lung adenocarcinoma cells to ferroptosis [161] . In addition, circRNA (Denticleless E3 Ubiquitin Protein Ligase Homolog) circDTL could act as a oncogene in lung cancer cells.…”