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

Authors

Wangsheng Chen, Xu Zhang, Zhengfei Zhao, Wang Xin, Jianxin Li, Xiangming Che

Published in

Cancer biology & therapy. Volume 27. Issue 1. Pages 2677975. Dec 31, 2026. Epub Jun 21, 2026.

Abstract

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.
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.
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.

PMID:
42324593
Bibliographic data and abstract were imported from PubMed on 22 Jun 2026.

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