A small molecule induces integrin β4 nuclear translocation and apoptosis selectively in cancer cells with high expression of integrin β4

Abstract

Increased integrin β4 (ITGB4) level is accompanied by malignant progression of multiple carcinomas. However, selective therapeutic strategies against cancer cells expressing a high level of ITGB4 have not been reported. Here, for the first time, we report that a chiral small molecule, SEC, selectively promotes apoptosis in cancer cells expressing a high level of ITGB4 by inducing ITGB4 nuclear translocation. Nuclear ITGB4 can bind to the ATF3 promoter region and activate the expression of ATF3, then upregulate the downstream pro-apoptosis genes. Furthermore, SEC promoted the binding of annexin A7 (ANXA7) to ITGB4 and increased ANXA7 GTPase activity. Activated ANXA7 promoted ITGB4 nuclear translocation by triggering ITGB4 phosphorylation at Y1494. SEC also inhibited the growth of xenograft tumors in the avian embryo model. We identified a small molecule, SEC, with selective pro-apoptosis effects on cancer cells with high expression of ITGB4, both in vitro and in vivo, by triggering the binding of ITGB4 and ANXA7, ITGB4 nuclear trafficking, and pro-apoptosis gene expression.

Plectin protects podocytes from adriamycin‐induced apoptosis and F‐actin cytoskeletal disruption through the integrin α6β4/FAK/p38 MAPK pathway

“…According to the molecular spatial conformation that plectin binds to integrin β4, we speculate that, when plectin is bound to integrin β4, the Y1494 site in the FNIII‐3 domain of integrin β4 is covered in the loop structure and cannot be phosphorylated. When plectin is down‐regulated and dissociates from integrin β4, the spatial conformation of the C‐terminus of β4 changes, leaving the loop structure open to a linear structure . At this time, Y1494 residue at the FNIII‐3 domain of β4 is exposed and can be phosphorylated.…”

“…When plectin is downregulated and dissociates from integrin β4, the spatial conformation of the C-terminus of β4 changes, leaving the loop structure open to a linear structure. 49,50 At this time, Y1494 residue at the FNIII-3 domain of β4 is exposed and can be phosphorylated. Thus, it is reasonable to speculate that plectin-integrin α6β4 binding may maintain Y1494 in an inhibited state and that loss of plectin-integrin α6β4…”

Responses of A549 human lung epithelial cells to cristobalite and α-quartz exposures assessed by toxicoproteomics and gene expression analysis

“…4(A) demonstrates that more than half of the proteins (e.g., ALDH1A1, ANXA7, CCT5, HTRA2 and PRDX6) involved in the cell death pathway in A549 cells are differently altered in A549 cells due to CR and MI exposures. The GTPase calcium-dependent phospholipid-binding protein ANXA7 can act as an anti-apoptotic protein (Huang et al, 2014(Huang et al, , 2015Liu et al, 2016;Torosyan et al, 2009), whereas HTRA2 (or OMI) is a proapoptotic serine peptidase that is known to cleave inhibitors of apoptosis to facilitate the activation caspase 3 (Cory & Adams, 2002;Sutton et al, 2003;Wang et al, 2013). Increased expression of the pro-apoptotic protein HTRA2 and decreased expression of the anti-apoptotic protein ANXA7 following particle exposures suggested that both silica particles could stimulate apoptotic cell death, which were consistent with the LDH release assay ( Fig.…”

Identification of prognostic and bone metastatic alternative splicing signatures in bladder cancer

“…Genetic experiments suggested that tumor cells might be more dependent on specific integrin than normal cells and might be regulated by integrin signals at different stages of tumor progression [28]. Integrin Beta 4 (ITGB4) was the structural component that maintains the hemidesmosomes (HDs) of the epithelial architecture [29]. It was the laminin receptor in tumor cells and angiogenic endothelial cells [30].…”

“…Integrin beta4 was characterized by its 1017-amino acid long domain in the beta4 subunit which paired only with the α6 subunit, and the heterodimeric integrin α6β4 played a role in the invasive and metastatic phenotype of various cancers [28,31,32]. Previous studies showed that ITGB4 was highly expressed in a variety of tumors [29,33]. It participated in the proliferation, invasion and metastasis [34][35][36], and also associated with poor prognosis of some tumors [37,38].…”