Journal
CANCER LETTERS
Volume 517, Issue -, Pages 14-23Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.05.040
Keywords
Bcl-xL; PAR2; EGFR; Colorectal cancer; RNF152
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Funding
- National Nature Sci-ence Foundation of China [81472560, 81672451,81672891, 81970467]
- CAMS Innovation Fund for Medical Sciences (CIFMS) [2016I2M1001,2017I2M1006, 2019I2M1003]
- National Key research and development program of the Ministry of Science and Technology of China [2016YFC0905301]
- State key laboratory of molecular oncology
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The study revealed a positive association between the tumor protein Bcl-xL and protease-activated receptor 2 (PAR2) in colorectal carcinoma. Activation of PAR2 stabilizes Bcl-xL by altering RNF152 signaling, and inhibition of PAR2 increases colorectal cancer sensitivity to EGFR-targeted therapies.
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 BclxL 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.
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