Cirsiliol targets tyrosine kinase 2 to inhibit esophageal squamous cell carcinoma growth in vitro and in vivo

Abstract

Background Esophageal squamous cell carcinoma (ESCC) is an aggressive and lethal cancer with a low 5 year survival rate. Identification of new therapeutic targets and its inhibitors remain essential for ESCC prevention and treatment. Methods TYK2 protein levels were checked by immunohistochemistry. The function of TYK2 in cell proliferation was investigated by MTT [(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and anchorage-independent cell growth. Computer docking, pull-down assay, surface plasmon resonance, and kinase assay were used to confirm the binding and inhibition of TYK2 by cirsiliol. Cell proliferation, western blot and patient-derived xenograft tumor model were used to determine the inhibitory effects and mechanism of cirsiliol in ESCC. Results TYK2 was overexpressed and served as an oncogene in ESCC. Cirsiliol could bind with TYK2 and inhibit its activity, thereby decreasing dimer formation and nucleus localization of signal transducer and activator of transcription 3 (STAT3). Cirsiliol could inhibit ESCC growth in vitro and in vivo. Conclusions TYK2 is a potential target in ESCC, and cirsiliol could inhibit ESCC by suppression of TYK2.

TYK2 in Cancer Metastases: Genomic and Proteomic Discovery

“…In various cancers, TYK2 overexpression or GOF mutations lead to STAT1 or STAT3 activation and upregulation of anti-apoptotic proteins, including B-cell CLL/lymphoma-2 (BCL-2) and myeloid cell leukaemia-1 (MCL-1) [20,41]. Recent reports investigated the pro-survival mechanisms of TYK2 signaling using pharmacologic or genetic inhibition of TYK2 or STAT3 in various cancer cell lines and mouse tumor models [20,41,106,107]. In human ALCL cells, inhibition of TYK2 by small molecule inhibitors or genetic depletion decreased proliferation and induced apoptosis with concomitant reductions in STAT1/STAT3 activation, MCL-1, IL-22 and IL-10 [41].…”

“…TYK2 deficiency reduces MPNST tumor growth through decreased proliferation and increased apoptosis mediated via lower phosphorylated STAT3 (p-STAT3) and BCL-2 with a concomitant increase in caspase 3 cleavage [20]. In esophageal cancer, TYK2 is also overexpressed, and associated with later stages of disease and shorter patient survival [106]. The flavonoid cirsiliol blocks TYK2-STAT3 induced cell proliferation and patient-derived xenograft (PDX) esophageal cancer tumor growth, likely through decreased C-MYC, BCL-2 and MCL-1 protein levels [106].…”

“…In esophageal cancer, TYK2 is also overexpressed, and associated with later stages of disease and shorter patient survival [106]. The flavonoid cirsiliol blocks TYK2-STAT3 induced cell proliferation and patient-derived xenograft (PDX) esophageal cancer tumor growth, likely through decreased C-MYC, BCL-2 and MCL-1 protein levels [106]. Fibroblast growth factor-2 (FGF-2) activates TYK2 to stimulate proliferation and protect osteosarcoma cells from chemotherapeutic drugs in vitro [107].…”

“…Other STAT target genes are involved in cancer signaling to regulate cell proliferation (e.g., cyclin D, HSP90), apoptosis (e.g., BCL-2, MCL-1, Bcl-xL), angiogenesis (e.g., VEGF-A, FGF), metastasis (e.g., MMP1-3, Vimentin, ICAM-1) and signaling (e.g., AKT, PI3K, TNF-R2) [113]. [18,20,41,106,108,109] while stimulating proliferation [20,41,106,108,113], migration, invasion [113][114][115][116][117][118], and resistance to chemotherapy [107]. These functions of TYK2 lead to increased tumor aggressiveness and metastasis [14,20,22,36,106], resulting in greater patient mortality.…”

Daurisoline Suppresses Growth of Esophageal Squamous Cell Carcinoma by Inhibiting MEK1/2 In Vitro and In Vivo

“…Active MEK1/2 proteins (250 ng) and KYSE150/450 cells lysates (500 μg) were bind to daurisoline-4B sepharose beads. See the previous experiments for details [24].…”