Journal of translational medicine · 2026
Exosome-delivered pepDCBLD2 promotes glucose metabolism to induce chemoresistance in colon cancer.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Wang Xinyi, Yang Jiayu, Yang Haiou, Xu Yue, Wang Huiya, Sun Mengyu, Gao Ming, Wang Ye, Zhang Haiyang
Аннотация
BACKGROUND: Oxaliplatin is a standard treatment for colon cancer, but chemoresistance is a considerable challenge. Dysregulation of circRNAs is involved in cancer and translatomics has found that some circRNAs encode polypeptides.
METHODS: Ribosome footprint profiling combined with circRNA sequencing was applied to screen circRNA with coding potential. Immunoprecipitation and mass spectrum were performed to explore the potential mechanism for regulating the downstream pathway. Ultracentrifugation and commercial kits were utilized to extract exosomes. Different kits were used to detect metabolic indexes. CCK-8, immunofluorescence and flow cytometry were conducted for the examination of oxaliplatin sensitivity. A xenograft model in NCG mice was established to demonstrate the pathway in vivo.
RESULTS: circDCBLD2 could encode pepDCBLD2 through rolling circle translation. pepDCBLD2, instead of the circRNA itself, participated in competitive binding to ubiquitin protein ligases, and upregulated the expression of the parent gene DCBLD2. Additionally, exosomes from drug resistant cells transferred pepDCBLD2 to sensitive cells, where it intercellularly regulated the DCBLD2/ERK/PKM2 pathway. This enhanced the glucose metabolism and reactive oxygen species scavenging capacity, ultimately promoting chemoresistance.
CONCLUSIONS: Exosome-delivered pepDCBLD2 encoded by circDCBLD2 promoted glucose metabolism to induce oxaliplatin resistance through the DCBLD2/ERK/PKM2 axis, which might be a potential therapeutic target for future treatment of chemoresistant colon cancer.
METHODS: Ribosome footprint profiling combined with circRNA sequencing was applied to screen circRNA with coding potential. Immunoprecipitation and mass spectrum were performed to explore the potential mechanism for regulating the downstream pathway. Ultracentrifugation and commercial kits were utilized to extract exosomes. Different kits were used to detect metabolic indexes. CCK-8, immunofluorescence and flow cytometry were conducted for the examination of oxaliplatin sensitivity. A xenograft model in NCG mice was established to demonstrate the pathway in vivo.
RESULTS: circDCBLD2 could encode pepDCBLD2 through rolling circle translation. pepDCBLD2, instead of the circRNA itself, participated in competitive binding to ubiquitin protein ligases, and upregulated the expression of the parent gene DCBLD2. Additionally, exosomes from drug resistant cells transferred pepDCBLD2 to sensitive cells, where it intercellularly regulated the DCBLD2/ERK/PKM2 pathway. This enhanced the glucose metabolism and reactive oxygen species scavenging capacity, ultimately promoting chemoresistance.
CONCLUSIONS: Exosome-delivered pepDCBLD2 encoded by circDCBLD2 promoted glucose metabolism to induce oxaliplatin resistance through the DCBLD2/ERK/PKM2 axis, which might be a potential therapeutic target for future treatment of chemoresistant colon cancer.