β ‐ arrestin 2 promotes 5 ‐ FU ‐ induced apoptosis via the NF ‐ κ B pathway in colorectal cancer

It has been demonstrated that β-arrestin2 is involved in the initiation and development of many types of cancers. However, its role in colorectal cancer (CRC) remains poorly understood. The present study investigated the role of β-arrestin2 in CRC using CRC patient tissues as well as the LoVo and HCT116 CRC cell lines. Briefly, significantly higher expression of β-arrestin2 was observed in CRC tissues compared with normal colon tissues. In addition, the downregulation of β-arrestin2 reduced 5-FU-induced apoptosis in the LoVo cells, while the overexpression of β-arrestin2 increased the apoptosis of HCT116 cells in vitro. Furthermore, the downregulation of β-arrestin2 reduced the expression of the pro-apoptotic proteins cleaved-caspase-3 and Bax, and increased the expression of the anti-apoptotic protein Bcl-2 after 5-FU treatment. In addition, the expression of p-p65 was increased after the β-arrestin2 downregulation and was decreased after the β-arrestin2 overexpression. However, β-arrestin2 downregulation had no effect on the proliferation, migration and invasion capacity of the LoVo cells. In conclusion, these results indicated that β-arrestin2 promoted 5-FU-induced CRC cell apoptosis via the NF-κB pathway and may be used as a prognosis marker for CRC. Introduction Colorectal cancer (CRC) is the third most common malignancy and one of the leading causes of cancer-related deaths worldwide (1-3). The global burden of CRC is increasing and is likely to persist until the year 2035 and beyond (4). With the introduction of CRC screening, more and more patients benefit from the early detection of precancerous lesions. However, despite the developments in colonoscopy as well as in treatment, the therapeutic effect of CRC remains unsatisfactory. The main obstacles in CRC therapy are metastasis and drug resistance. Therefore, understanding the molecular mechanism of CRC is important for the development of an effective therapy. β-arrestin1 and β-arrestin2 belong to the nonvisual β-arrestins and are ubiquitous proteins. β-arrestins are multifunctional proteins and are well-known for their classical role in the G protein-coupled receptor (GPCR) desensitization, sequestration and internalization (5,6). Furthermore, β-arrestins are scaffold proteins that can interact with many other signaling molecules and regulate cellular responses, such as proliferation, migration and invasion as well as apoptosis (7,8). β-arrestins play an important role in physiological and pathological conditions. Numerous studies have demonstrated that β-arrestin2 is abnormally expressed in many types of cancer, including breast, lung, castration-resistant prostate and hepatocellular cancer (9,10). β-arrestin2 is essential for the tumorigenesis of chronic myelogenous leukemia and colon cancer (11,12). It contributes to the proliferation of castration-resistant prostate cancer but inhibits lung cancer growth (13,14). It also decreases metastasis of hepatocellular cancer, but promotes breast cancer migration and invasion (15,16). Above all, β-arrestin2 is involved in the tumorigenesis and progression of cancer in multifunctional ways. Bonnans et al (12) demonstrated that β-arrestin2 is required for the initiation of colon cancer through the elevated Wnt pathway in vivo and in vitro (12). Nonetheless, the expression and clinicopathological significance of β-arrestin2 in CRC have not been reported. Liu et al (17) demonstrated that β‐arrestin2 deficiency protracts the activation of the NF‐κB pathway and suppresses radiation-induced intestinal crypt progenitor cell apoptosis (17). However, the role of β-arrestin2 β‐arrestin2 promotes 5‐FU‐induced apoptosis via the NF‐κB pathway in colorectal cancer WEIXIA REN1,2, TINGTING WANG2, XIANGJUN HE1, QI ZHANG1, JIANHUA ZHOU1, FANGFANG LIU3, FANGFANG GAO1, YUJUN ZHANG1 and YULAN LIU1,2 1Institute of Clinical Molecular Biology and Central Laboratory, and Departments of 2Gastroenterology and 3Pathology, Peking University, People's Hospital, Beijing 100044, P.R. China Received May 9, 2017; Accepted March 12, 2018 DOI: 10.3892/or.2018. 6340 Correspondence to: Dr Yujun Zhang, Institute of Clinical Molecular Biology and Central Laboratory, Peking University, People's Hospital, 11 South Avenue, Xi Zhi Men, Xicheng, Beijing 100044, P.R. China E-mail: zhangyujun@pkuph.edu. cn Dr Yulan Liu, Department of Gastroenterology, Peking University, People's Hospital, 11 South Avenue, Xi Zhi Men, Xicheng, Beijing 100044, P.R. China E-mail: liuyulan@pkuph.edu. cn Abbreviations: CRC, colorectal cancer; siRNA, small interfering RNA; NC, negative control; GPCR, G protein-coupled receptor; PCR, polymerase chain reaction; NSCLC, non-small cell lung