PELI1 promotes radiotherapy sensitivity by inhibiting noncanonical NF-κB in esophageal squamous cancer.

The low sensitivity of radiotherapy is the main cause of tumor tolerance against ionizing radiation (IR). However, the molecular mechanisms by which radiosensitivity is controlled remain elusive. Here, we observed that high expression of pellino E3 ubiquitin protein ligase 1 (PELI1) was correlated with improved prognosis in human esophageal squamous cell carcinoma stage III patients that received adjuvant radiotherapy. Moreover, we found PELI1-mediated IR-induced tumor cell apoptosis in vivo and in vitro. Mechanistically, PELI1 mediated the lysine 48 (Lys48)-linked polyubiquitination and degradation of NF-κB-inducing kinase (NIK; also known as MAP3K14), the master kinase of the noncanonical NF-κB pathway, thereby inhibiting IR-induced activation of the noncanonical NF-κB signaling pathway during radiotherapy. As a consequence, PELI1 inhibited the noncanonical NF-κB-induced expression of the anti-apoptotic gene BCL2 like 1 (Bclxl; also known as BCL2L1), leading to an enhancement of the IR-induced apoptosis signaling pathway and ultimately promoting IR-induced apoptosis in tumor cells. Therefore, Bclxl or NIK knockdown abolished the apoptosis-resistant effect in PELI1-knockdown tumor cells after radiotherapy. These findings establish PELI1 as a critical tumor intrinsic regulator in controlling the sensitivity of tumor cells to radiotherapy through modulating IR-induced noncanonical NF-κB expression.