2. Academic Validation
  3. Protease-activated receptor 2 stabilizes Bcl-xL and regulates EGFR-targeted therapy response in colorectal cancer

Protease-activated receptor 2 stabilizes Bcl-xL and regulates EGFR-targeted therapy response in colorectal cancer

  • Cancer Lett. 2021 Oct 1;517:14-23. doi: 10.1016/j.canlet.2021.05.040.
Weiwei Li 1,  Yiming Ma 1,  Longmei He 1,  Hongwei Li 2,  Yi Chu 2,  Zheng Jiang 3,  Xinhua Zhao 1,  Yongzhan Nie 2,  Xishan Wang 3,  Hongying Wang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
  • 2 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.
  • 3 Department of Colorectal Cancer Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
  • 4 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. Electronic address: hongyingwang@cicams.ac.cn.
PMID: 34098062 DOI: 10.1016/j.canlet.2021.05.040
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.

Keywords

Bcl-xL; Colorectal cancer; EGFR; PAR2; RNF152.

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