ADAR1-circRAB5A-BIP axis governs radiotherapy resistance in colorectal cancer through coordinating protective autophagy and apoptosis.

Abstract

Background: Colorectal cancer (CRC) ranks among the most prevalent malignancies globally, and radiotherapy remains a critical treatment modality. However, its efficacy is frequently compromised by acquired radioresistance. The endoplasmic reticulum chaperone protein BIP plays a pivotal role in regulating radioresistance by coordinating the balance between protective autophagy and apoptosis, though the regulatory roles of circular RNAs (circRNAs) in this process remain poorly understood.

Materials: Differentially expressed circRAB5A (hsa-circ-0123297) was identified from the GSE186940 dataset. Its expression was validated in radioresistant CRC clinical samples and cell lines. Mechanistic investigations involved ADAR1 binding assays, circRAB5A gain/loss-of-function studies, autophagy-apoptosis profiling, ubiquitination analysis, TRIM21-mediated degradation assays, and in vivo xenograft models.

Results & conclusion: CircRAB5A was significantly downregulated in radioresistant CRC clinical samples and cell lines. This downregulation was driven by ADAR1, which suppressed circRAB5A biogenesis by binding to Alu Jo/Jr elements. Functional assays showed circRAB5A depletion conferred radioresistance in CRC cells by promoting protective autophagy and inhibiting apoptosis. Mechanistically, circRAB5A destabilized BIP by enhancing TRIM21-mediated ubiquitination. The circRAB5A/BIP axis further modulates the autophagy-apoptosis balance through the p-Akt/Beclin1 signaling pathway, thereby influencing radiosensitivity. In vivo xenograft experiments demonstrated that stable knockdown of circRAB5A attenuated the anti-tumor effects of radiation, whereas knockdown of BIP sensitized CRC cells to radiotherapy even at low doses. Collectively, the ADAR1/circRAB5A/BIP molecular circuitry governs CRC radioresistance by regulating the autophagy-apoptosis balance. Our findings highlight that low circRAB5A expression may serve as a potential biomarker for radioresistance, and that targeting this axis, particularly BIP, represents a promising strategy for overcoming radioresistance in CRC.