Title

A novel platinum compound inhibits constitutive Stat3 signaling and induces cell cycle arrest and apoptosis of malignant cells

Authors

Authors

J. Turkson; S. M. Zhang; L. B. Mora; A. Burns; S. Sebti;R. Jove

Comments

Authors: contact us about adding a copy of your work at STARS@ucf.edu

Abbreviated Journal Title

J. Biol. Chem.

Keywords

BREAST-CARCINOMA CELLS; CANCER DRUG DISCOVERY; DNA-BINDING ACTIVITY; HUMAN SERUM-ALBUMIN; U266 MYELOMA CELLS; MOLECULAR TARGETS; SRC; ONCOPROTEIN; KINASE-ACTIVITY; GENE-REGULATION; TRANSCRIPTIONAL; ACTIVATION; Biochemistry & Molecular Biology

Abstract

Previous studies have established constitutive activation of Stat3 protein as one of the molecular changes required for tumorigenesis. To develop novel therapeutics for tumors harboring constitutively active Stat3, compounds from the NCI 2000 diversity set were evaluated for inhibition of Stat3 DNA-binding activity in vitro. Of these, a novel platinum (IV) compound, IS3 295, interacted with Stat3 and inhibited its binding to specific DNA-response elements. Further analysis suggested noncompetitive-type kinetics for the inhibition of Stat3 binding to DNA. In human and mouse tumor cell lines with constitutively active Stat3, IS3 295 selectively attenuated Stat3 signaling, thereby inducing cell growth arrest at G(0)/G(1) phase and apoptosis. Moreover, in transformed cells, IS3 295 repressed expression of cyclin D1 and bcl-x(L), two of the known Stat3-regulated genes that are overexpressed in malignant cells, suggesting that IS3 295 mediates anti-tumor cell activity in part by blocking Stat3-mediated subversion of cell growth and apoptotic signals. Together, our findings provide evidence for the inhibition of Stat3 activity and biological functions by IS3 295 through interaction with Stat3 protein. This study represents a significant advance in small molecule-based approaches to target Stat3 and suggests potential new applications for platinum (IV) complexes as modulators of the Stat3 pathway for cancer therapy.

Journal Title

Journal of Biological Chemistry

Volume

280

Issue/Number

38

Publication Date

1-1-2005

Document Type

Article

Language

English

First Page

32979

Last Page

32988

WOS Identifier

WOS:000231920300052

ISSN

0021-9258

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