Abstract
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) occurs in ∼70% of human cancers, and STAT3 is regarded as one of the most promising targets for cancer therapy. However, specific direct STAT3 inhibitors remain to be developed. Oridonin is an ent-kaurane plant-derived diterpenoid with anti-cancer and anti-inflammatory activities. Here, using an array of cell-based and biochemical approaches, including cell proliferation and apoptosis assays, pulldown and reporter gene assays, site-directed mutagenesis, and molecular dynamics analyses, we report that a thiazole-derived oridonin analogue, CYD0618, potently and directly inhibits STAT3. We found that CYD0618 covalently binds to Cys-542 in STAT3 and suppresses its activity through an allosteric effect, effectively reducing STAT3 dimerization and nuclear translocation, as well as decreasing expression of STAT3-targeted oncogenes. Remarkably, CYD0618 not only strongly inhibited growth of multiple cancer cell lines that harbor constitutive STAT3 activation, but it also suppressed in vivo tumor growth via STAT3 inhibition. Taken together, our findings suggest Cys-542 as a druggable site for selectively inhibiting STAT3 and indicate that CYD0618 represents a promising lead compound for developing therapeutic agents against STAT3-driven diseases.
Highlights
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) occurs in ϳ70% of human cancers, and STAT3 is regarded as one of the most promising targets for cancer therapy
A series of cytokines and growth factors. Once ligands such as interleukin 6 (IL-6) and epidermal growth factor (EGF) bind to their receptors, STAT3 can be phosphorylated by the Janus kinases (JAKs), receptor tyrosine kinases (e.g. EGFR), or nonreceptor tyrosine kinases (e.g. Src) at tyrosine 705 (Tyr-705)
To assess the inhibitory activity of CYD0618 (Fig. 1A) on ovarian cancer, we examined the impact of CYD0618 on four human ovarian cancer cell lines, including A2780, OVCAR3, OVCAR8, and SKOV3 via sulforhodamine B (SRB) staining [25]
Summary
A thiazole-derived oridonin analogue exhibits antitumor activity by directly and allosterically inhibiting STAT3. A series of phosphate dehydrogenase; PARP, poly(ADP-ribose) polymerase; SRB, sulforhodamine B; EGFR, EGF receptor; PPB, phosphorylated peptide; PB, nonphosphorylated peptide; SH2, Src homology 2; DBD, DNA-binding domain; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling; JAK, Janus kinase; IL-6, interleukin 6; IFN-␥, interferon-␥; PDB, Protein Data Bank; TNBC, triple-negative breast cancer; DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; PI, propidium iodide; co-IP, co-immunoprecipitation; PMSF, phenylmethylsulfonyl fluoride; MD, molecular dynamics; PTP, protein-tyrosine phosphatase; CYDNC, CYD0618-negative control; H&E, hematoxylin and eosin. These findings uncover that CYD0618 is a potent direct STAT3 inhibitor, and revealed that Cys542 in the linker domain is a druggable binding site for selectively targeting STAT3
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