TTI1 contributes to radioresistance by activating ATM pathway in rectal cancer.

BACKGROUND: TTI1 has been reported as a critical protein in oncogenesis, migration and invasion of various cancers. And its expression level was increased in rectal cancer (RC). However, the biological role of TTI1 in RC is unclear. In the course of exploratory study, we found that TTI1 expression was elevated in radioresistant RC. Therefore, the study was designed to investigate the role of TTI1 in the radiotherapy of RC.

METHODS: The proliferative activity of RC cells treated by irradiation was performed using MTT assay and colony formation assay in vitro as well as nude mouse tumour xenograft assay in vivo. Various methods including western blot, qRT-PCR, flow cytometry, and comet assay were used to exploring the molecular mechanism of TTI1 in radiotherapy of RC. The organoid and PDX models were used to analyse the radiotherapy sensitization effect of suppressing ATM signaling pathway.

RESULTS: TTI1 expression was significantly increased in radioresistant RC. The clinical study demonstrated that significantly elevated TTI1 expression resulted in a poor tumour response in RC patients treated with irradiation. TTI1 knockdown could enhance sensitivity of RC cells to irradiation while TTI1 overexpression had the opposite effect. TTI1 could enhance irradiation-induced DNA damage repair through activating ATM signaling pathway. Blocking ATM signaling pathway could enhance the sensitivity of RC tissue to irradiation.

CONCLUSIONS: TTI1 was identified as a critical factor in regulating resistance of RC to irradiation. TTI1 could be regarded as a credible biomarker for predicting radiotherapeutic effect and prognosis. Inhibition of ATM signaling pathway may be a novel method to overcome radioresistance.