Radiotherapy resistance remains the major factor limiting the radiotherapy efficacy in colorectal cancer. The Mre11-RAD50-Nbs1 (MRN) complex is known to play a critical role in the DNA double strand breaks (DSBs) repair pathways and thus facilitates radioresistance. Targeting MRN function can sensitize cancer cells to irradiation in some malignancies. In this study, we stably knocked down RAD50 protein in colorectal cancer (CRC) cell lines, HCT116 and DLD1, and evaluated their response to irradiation as well as the DSB repair dynamics. We observed that downregulation of RAD50 sensitized CRC cells to irradiation with reduction in DSB repair efficiency after exposure to irradiation. In addition, RAD50 was found to be upregulated in CRC cancerous tissue samples compared to non-cancerous adjacent tissues (NATs) and in patients who were resistant to RT. Elevated RAD50 expression was associated with poor patient survival in CRC. In conclusion, targeting RAD50 can serve as an efficient strategy to sensitize CRC cells to irradiation. RAD50 protein may be used as a biomarker for patient survival in CRC.

No abstract

Colorectal cancer (CRC) metastasis plays a crucial role in disease progression, yet the regulatory mechanisms underlying metastasis remain incompletely understood. Isobutyric acid (IBA), a short‐chain fatty acid found at high levels in serum of CRC patients, has been shown to be a critical metabolite influencing CRC proliferation. However, its role in tumor metastasis remains unknown. Here, utilizing liquid chromatography tandem mass spectrometry (LC‐MS/MS) analysis, we found that levels of IBA were significantly higher in patients with distant organ metastasis of CRC than in those without. Furthermore, IBA promoted CRC metastasis both in vitro and in vivo. Mass spectrometry, immunofluorescence, and cellular thermal shift assay revealed that IBA interacts with RACK1. Mechanistically, IBA binding to and activating RACK1 promotes regulation of downstream Akt and FAK signaling and CRC metastasis. Collectively, our study highlights the critical interplay between IBA and RACK1 and its impact on tumor metastasis. This study suggests that targeting the IBA–RACK1 signaling axis may be an effective therapeutic strategy for controlling CRC metastasis.