Dataset Information

Monomerization of Homodimeric Trefoil Factor 3 (TFF3) by an Aminonitrile Compound Inhibits TFF3-Dependent Cancer Cell Survival.

ABSTRACT: Trefoil factor 3 (TFF3) is a secreted protein with an established oncogenic function and a highly significant association with clinical progression of various human malignancies. Herein, a novel small molecule that specifically targets TFF3 homodimeric functions was identified. Utilizing the concept of reversible covalent interaction, 2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AMPC) was identified as a molecule that interacted with TFF3. AMPC monomerized the cellular and secreted TFF3 homodimer at the cysteine (Cys)57-Cys57 residue with subsequent more rapid degradation of the generated TFF3 monomers. Hence, AMPC treatment also resulted in cellular depletion of TFF3 with consequent decreased cell viability in various human carcinoma-derived TFF3 expressing cell lines, including estrogen receptor positive (ER+) mammary carcinoma (MC). AMPC treatment of TFF3 expressing ER+ MC cells significantly suppressed total cell number in a dose-dependent manner. Consistently, exposure of TFF3 expressing ER+ MC cells to AMPC decreased soft agar colony formation, foci formation, and growth in suspension culture and inhibited growth of preformed colonies in 3D Matrigel. AMPC increased apoptosis in TFF3 expressing ER+ MC cells associated with decreased activity of EGFR, p38, STAT3, AKT, and ERK, decreased protein levels of CCND1, CCNE1, BCL2, and BCL-XL, and increased protein levels of TP53, CDKN1A, CASP7, and CASP9. siRNA-mediated depletion of TFF3 expression in ER+ MC cells efficiently abrogated AMPC-stimulated loss of cell viability and CASPASE 3/7 activities. Furthermore, in mice bearing ER+ MC cell-generated xenografts, AMPC treatment significantly impeded xenograft growth. Hence, AMPC exemplifies a novel mechanism by which small molecule drugs may inhibit a dimeric oncogenic protein and provides a strategy to impede TFF3-dependent cancer progression.

SUBMITTER: Pandey V

PROVIDER: S-EPMC9469493 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Monomerization of Homodimeric Trefoil Factor 3 (TFF3) by an Aminonitrile Compound Inhibits TFF3-Dependent Cancer Cell Survival.

Pandey Vijay V Zhang Xi X Poh Han-Ming HM Wang Baocheng B Dukanya Dukanya D Ma Lan L Yin Zhinan Z Bender Andreas A Periyasamy Ganga G Zhu Tao T Rangappa Kanchugarakoppal S KS Basappa Basappa B Lobie Peter E PE

ACS pharmacology & translational science 20220817 9

Trefoil factor 3 (TFF3) is a secreted protein with an established oncogenic function and a highly significant association with clinical progression of various human malignancies. Herein, a novel small molecule that specifically targets TFF3 homodimeric functions was identified. Utilizing the concept of reversible covalent interaction, 2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5H-pyrano[3,2-<i>c</i>]chromene-3-carbonitrile (AMPC) was identified as a molecule that interacted wit ...[more]

PMID: 36110371

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Project description:ObjectivesTrefoil factor 3 (TFF3) is a small peptide that plays an important role in mucosal protection, cell proliferation, and cell migration. The aberrant expression of TFF3 is correlated with gastrointestinal inflammation, solid tumors, and other clinical diseases. The objective of this study was to identify the distribution characteristics of serum TFF3 in common clinical diseases.Materials and methodsA large prospective randomized study of 1,072 Chinese patients was performed using an enzyme-linked immunosorbent assay (ELISA) to examine the serum TFF3 concentrations in patients with different diseases. A matched case-control study was conducted on patients with chronic kidney disease (CKD) stages 1-5. Immunohistochemistry (IHC) was performed using renal tissues to determine the relationship between the severity of CKD and the serum and urine concentrations of TFF3 peptides.ResultsThe mean serum concentrations of TFF3 in patients with CKD, metastatic and secondary carcinoma (MC) and acute gastroenteritis (AG) (200.9 ng/ml, 95.7 ng/ml and 71.7 ng/ml, respectively) were significantly higher than those in patients with other common clinical diseases. A positive correlation tendency was observed between the serum TFF3 concentrations and the severity of CKD. The mean serum TFF3 values for CKD stages 1-5 were 23.6 ng/ml, 29.9 ng/ml, 54.9 ng/ml, 85.0 ng/ml and 176.6 ng/ml, respectively. The same trend was observed in the urine TFF3 concentrations and the CKD stages. The creatinine(Cr)-corrected concentrations of TFF3 in urine were 367.1 ng/mg·Cr, 910.6 ng/mg·Cr, 1,149.0 ng/mg·Cr, 1,610.0 ng/mg·Cr and 3,475.0 ng/mg·Cr for CKD stages 1-5, respectively. IHC revealed that TFF3 expression was concentrated in tubular epithelial cells.ConclusionsThe influence of kidney injuries must be fully considered when performing clinical TFF3 research. Further studies on TFF3 in CKD will contribute to our understanding of its pathological roles and mechanisms in other diseases.

Dataset Information

Monomerization of Homodimeric Trefoil Factor 3 (TFF3) by an Aminonitrile Compound Inhibits TFF3-Dependent Cancer Cell Survival.

Publications

Monomerization of Homodimeric Trefoil Factor 3 (TFF3) by an Aminonitrile Compound Inhibits TFF3-Dependent Cancer Cell Survival.

Similar Datasets

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