Protease-activated receptor 2 stabilizes Bcl-xL and regulates EGFR–targeted therapy response in colorectal cancer
Weiwei Li, Yiming Ma, Longmei He, Hongwei Li, Yi Chu, Zheng Jiang, Xinhua Zhao, Yongzhan Nie, Xishan Wang, Hongying Wang
Abstract
The Bcl-2 homolog Bcl-xL is emerging as a key factor in tumorigenesis due to its prominent pro-survival and cell death-independent functions. However, the regulation of Bcl-xL by microenvironment and its implication in cancer therapy of colorectal carcinoma (CRC) are unclear. Here, we demonstrated that Bcl-xL expression was positively associated with protease-activated receptor 2 (PAR2) in CRC. Activation of PAR2 stabilized Bcl-xL protein in a proteasome-dependent manner, whereas E3 ligase RING finger protein 152 (RNF152) accelerated the ubiquitination and degradation of Bcl-xL. RNF152 silencing by specific siRNAs rescued the expression of Bcl-xL in PAR2-deficient cells. Moreover, RNF152 physically interacted with Bcl-xL, which was disturbed by PAR2 activation. Further studies with serial mutation of Bcl-xL revealed that phosphorylation of Bcl-xL at S145 reduced its binding affinity for RNF152 and stabilized Bcl-xL. Importantly, inhibition of PAR2 signaling by its gene silencing or specific chemical inhibitors increased apoptosis induced by different EGFR-targeted therapies. In patient-derived xenograft model, inhibition of PAR2 increased the response of CRC to different EGFR-targeted therapies. These results indicate that PAR2 stabilizes Bcl-xL by altering RNF152 signaling and that PAR2 inhibition sensitizes CRC to EGFR-targeted therapies in vivo.