β-arrestin Promotes c-Jun N-terminal Kinase Mediated Apoptosis via a GABA_BR·β-arrestin·JNK Signaling Module

Abstract

Asian Pac J Cancer Prev, 15 (2), 1041-1046 IntroductionAs one of the most common types of cancer, breast cancer represents the most prevalent and lethal malignancy among female. Its incidence in China has gradually increased accompanied with the changes in people's lifestyle (Wang et al., 2013). Despite developments in surgery and the increased number of drugs for radio-and chemotherapy, post-operative morbidity and other health problems significantly reduced the life quality of patients (Li et al., 2013). Thus, a better understanding of the molecular mechanism that drives breast cancer growth and invasion is required to promote development of more effective therapies for breast cancer patients.GABA, also known as γ-aminobutyric acid, was originally identified as a principal inhibitory neurotransmitter which widely distributes in the adult mammalian brain (Watanabe et al., 2002). There are three different types of GABA receptors including ionotropic receptor families GABA A R and GABA C R. GABA A R is commonly used as a drug target in clinical practice, while GABA C R is found exclusively in the retina. As G protein-coupled receptors (GPCR), GABA B receptors are seven trans-membrane receptors which are coupled to G-proteins to counteract the activity of betaadrenoreceptors (β-ARs) in the central nervous system via GABA B receptor-mediated inhibition of adenylyl cyclase (Chebib et al., 1999;Gladkevich et al., 2006

Structure and function of β-arrestins, their emerging role in breast cancer, and potential opportunities for therapeutic manipulation

“…Furthermore, the analysis of TCGA (The Cancer Genome Atlas) and METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) datasets reveal that βarr1 expression is downregulated in TNBC patient samples, further underscoring its role as a potential tumor suppressor in breast cancer (Son et al, 2019). Wu et al have reported that in MCF-7 and T-47D breast cancer cell lines, the levels of βarr2 is lower compared to corresponding control cell lines, and βarr2 overexpression inhibits proliferation of these cells and triggers apoptosis (Wu et al, 2014). The contribution of βarr2 in this context involves GABA-B receptor and activation of JNK kinase (Wu et al, 2014).…”

“…Wu et al have reported that in MCF-7 and T-47D breast cancer cell lines, the levels of βarr2 is lower compared to corresponding control cell lines, and βarr2 overexpression inhibits proliferation of these cells and triggers apoptosis (Wu et al, 2014). The contribution of βarr2 in this context involves GABA-B receptor and activation of JNK kinase (Wu et al, 2014). Another study has observed overexpression of an orphan GPCR, Gpr161, in MDA-MB-361 and BT-474 cells (Feigin et al, 2014).…”

“…Significantly reduces morphine-induced cell death in MCF-7 and MDA-MB231 cells via an Akt and caspase-8 pathways Zhao et al (2009) βarr1 and βarr2 Impair LPA-induced migration and invasion of MDA-MB-231 cells via a Ral GTPase mechanism Li et al (2009) βarr1 Comparatively higher expression in ERα + invasive ductal carcinoma compared to invasive ERα -ductal carcinomas Overexpression inhibits proliferation and promotes apoptosis of MCF-7 and T-47D cells via GABA B R/JNK pathway Wu, Shan, Zheng, and Pei (2014) βarr2…”

Emerging role of the Jun N‐terminal kinase interactome in human health

“…The GABAB receptor is involved in tumorigenesis; b-arrestin recruits JNK to the GABAB receptor, where it is activated and reduces the growth of cancer cells. This same method of JNK activation promotes cell apoptosis in breast cancer cells (Wu et al, 2014). In Drosophila, Kurtz is a non-visual arrestin equivalent that couples Methuselah (MTH), a GPCR required for neurosecretion, with JNK, thus mediating stress-resistance and longer life (Gimenez et al, 2013).…”