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Discovery of JSI-124 (Cucurbitacin I), a Selective Janus Kinase/Signal

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Discovery of JSI-124 (Cucurbitacin I), a Selective Janus Kinase/Signal [CANCER RESEARCH 63, 1270–1279, March 15, 2003] Discovery of JSI-124 (Cucurbitacin I), a Selective Janus Kinase/Signal Transducer and Activator of Transcription 3 Signaling Pathway Inhibitor with Potent Antitumor Activity against Human and Murine Cancer Cells in Mice1 Michelle A. Blaskovich,2 Jiazhi Sun,2 Alan Cantor, James Turkson, Richard Jove, and Saı¨d M. Sebti3 Drug Discovery Program [M. A. B., J. S., S. M. S.] and Molecular Oncology Program [J. T., R. J.], Biostatistics and Informatics Core [A. C.], H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, and Departments of Oncology and Biochemistry and Molecular Biology, University of South Florida, Tampa, Florida 33612 [M. A. B., J. S., J. T., R. J., S. M. S.] ABSTRACT Gene knockout and other experiments implicated STATs in many important physiological functions such as immune modulation, in- Constitutively activated, tyrosine-phosphorylated signal transducer flammation, proliferation, differentiation, development, cell survival, and activator of transcription (STAT) 3 plays a pivotal role in human and apoptosis (1–4). tumor malignancy. To discover disrupters of aberrant STAT3 signaling pathways as novel anticancer drugs, we developed a phosphotyrosine STAT tyrosine phosphorylation is required for the biological func- STAT3 cytoblot. Using this high throughput 96-well plate assay, we tion of STATs. This occurs when cytokines such as interleukin 6 and identified JSI-124 (cucurbitacin I) from the National Cancer Institute IFN or growth factors such as platelet-derived growth factor and Diversity Set. JSI-124 suppressed the levels of phosphotyrosine STAT3 in epidermal growth factor bind their respective receptors, which results v-Src-transformed NIH 3T3 cells and human cancer cells potently (IC50 in STAT protein recruitment to the inner surface of the plasma value of 500 nM in the human lung adenocarcinoma A549) and rapidly membrane in the vicinity of the cytoplasmic portion of the receptors (complete inhibition within 1–2 h). The suppression of phosphotyrosine (5, 6). Tyrosine kinases that are known to phosphorylate STATs are STAT3 levels resulted in the inhibition of STAT3 DNA binding and non-RTKs such as Src and the JAKs, JAK1 and JAK2. Other possible STAT3-mediated but not serum response element-mediated gene tran- tyrosine kinases that can phosphorylate STATs are peptide growth scription. JSI-124 also decreased the levels of tyrosine-phosphorylated Janus kinase (JAK) but not those of Src. JSI-124 was highly selective for factor receptors such as platelet-derived growth factor receptor and JAK/STAT3 and did not inhibit other oncogenic and tumor survival EGFR. The cellular levels of STATs that are tyrosine phosphorylated pathways such as those mediated by Akt, extracellular signal-regulated could also be regulated by phosphotyrosine STAT phosphatases such kinase 1/2, or c-Jun NH2-terminal kinase. Finally, JSI-124 (1 mg/kg/day) as SHP-1 and SHP-2 (7–9). Once tyrosine phosphorylated, STAT potently inhibited the growth in nude mice of A549 tumors, v-Src-trans- monomers dimerize via reciprocal phosphotyrosine-SH2 interactions formed NIH 3T3 tumors, and the human breast carcinoma MDA-MB-468, and translocate to the nucleus, where they bind DNA and regulate all of which express high levels of constitutively activated STAT3, but it gene transcription (3, 10). Whereas tyrosine phosphorylation of did not affect the growth of oncogenic Ras-transformed NIH 3T3 tumors STATs regulates dimerization, nuclear translocation and DNA bind- that are STAT3 independent or of the human lung adenocarcinoma ing, serine/threonine phosphorylation is believed to regulate the tran- Calu-1, which has barely detectable levels of phosphotyrosine STAT3. JSI-124 also inhibited tumor growth and significantly increased survival scriptional activity of STATs (11). of immunologically competent mice bearing murine melanoma with con- Several lines of evidence have implicated some STAT family stitutively activated STAT3. These results give strong support for phar- members in malignant transformation and tumor cell survival (12, 13). macologically targeting the JAK/STAT3 signaling pathway for anticancer STAT3 involvement in oncogenesis is the most thoroughly charac- drug discovery. terized. First, STAT3 is found constitutively tyrosine phosphorylated and activated in many human cancers (12–14). This abnormal activa- INTRODUCTION tion of STAT3 is prevalent in breast, pancreatic, ovarian, head and neck, brain, and prostate carcinomas, as well as in melanomas, leu- STATs4 are key signal transduction proteins that play a dual role of kemias, and lymphomas. In those tumors investigated, aberrant transducing biological information from cell surface receptors to the STAT3 activation is required for growth and survival (12–14). Sec- cytoplasm and translocating to the nucleus, where, as transcription ond, many known oncogenes, especially those belonging to the non- factors, they regulate gene expression (reviewed in Refs. 1–4). Mam- RTK family such as src, induce constitutive activation of STAT3 (15). malian cells express seven different STATs (1, 2, 3, 4, 5a, 5b, and 6). Third, expression of a constitutively activated mutant of STAT3, for which stable dimerization was forced through disulfide covalent link- Received 6/13/02; accepted 1/9/03. age, was shown to be sufficient to induce cell transformation and The costs of publication of this article were defrayed in part by the payment of page tumor growth in nude mice (16). Finally, perhaps the most compelling charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. evidence for the requirement of STAT3 for oncogenesis and its 1 Supported in part by National Cancer Institute Drug Discovery Program Project validation as an anticancer drug target comes from experiments in Grant CA78038. 2 These authors contributed equally to this work. which a dominant negative form of STAT3 was used in cultured cells 3 To whom requests for reprints should be addressed, at Drug Discovery Program, H. and in gene therapy animal experiments to show that blocking aber- Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL rant activation of STAT3 results in inhibition of tumor growth and 33612. Phone: (813) 979-6734; E-mail: [email protected]. 4 The abbreviations used are: JAK, Janus kinase; STAT, signal transducer and activator survival and induction of apoptosis with few side effects to normal of transcription; EGFR, epidermal growth factor receptor; NCI, National Cancer Institute; cells (17, 18). TBS, Tris-buffered saline [10 mM Tris (pH 7.4), 150 mM NaCl]; PMSF, phenylmethyl- On the basis of the above observations, we and others have pro- sulfonyl fluoride; MEK, mitogen-activated protein/extracellular signal-regulated kinase kinase; JNK, c-Jun NH2-terminal kinase; SRE, serum response element; RIPA, radioim- posed to target STAT3 for the development of novel anticancer drugs munoprecipitation assay; TUNEL, terminal deoxynucleotidyl transferase-mediated nick (reviewed in Refs. 12–14). Depending on the aberrant genetic alter- end labeling; EMSA, electrophoretic mobility shift analysis; ERK, extracellular signal- regulated kinase; PI3k, phosphatidylinositol 3Ј-kinase; RTK, receptor tyrosine kinase; ations that result in constitutively tyrosine-phosphorylated, activated SHP, SH2-containing phosphatase; DAP1, 4Ј-6-diamidino-2-phenylindole. STAT3, several approaches could be undertaken including blocking 1270 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2003 American Association for Cancer Research. DISCOVERY OF JSI-124, A JAK-STAT3 PATHWAY INHIBITOR ligand-receptor interactions, inhibiting receptor and non-RTKs, acti- 20 at a 1:1000 dilution for1hatroom temperature. Western blots were vating phosphotyrosine STAT3 phosphatases, and blocking STAT3 visualized using enhanced chemiluminescence as described previously (21). dimerization, nuclear translocation, DNA binding, and gene transcrip- Immunoprecipitation of STAT3. A549 cells were treated for 4 h with tion. In addition, gene therapy, antisense, or RNA interference ap- vehicle or JSI-124 and then lysed in 150 mM HEPES (pH 7.5), 150 mM NaCl, proaches can also be attempted. One approach that we have taken, the 1mM EDTA, 0.5% NP40, 10% glycerol, 5 mM NaF, 1 mM DTT, 1 mM PMSF, ␮ results of which are described in this study, is to identify small 2mM sodium orthovanadate, and 5 g/ml leupeptin. Sample lysates were collected and cleared, and then 500 ␮g of lysate were immunoprecipitated with molecules capable of interfering with the signaling events leading to 50 ng of STAT3 antibody overnight at 4°C and rocked with 25 ␮l of protein the abnormally elevated levels of tyrosine-phosphorylated STAT3 in A/G PLUS-agarose (Santa Cruz Biotechnology) for1hat4°C. Samples were many human cancer cells. washed four times with lysis buffer and then boiled in 2ϫ SDS-PAGE sample buffer and run on 10% SDS-PAGE gel. Protein was transferred to nitrocellu- MATERIALS AND METHODS lose and then blotted as described above for both phospho-specific STAT3 and STAT3. Cell Lines. All human and murine tumor cell lines used were obtained DNA Binding and Transcription. The STAT3 reporter, pLucTKS3, driv- from the American Type Culture Collection (Manassas, VA). Stably trans- ing expression of firefly luciferase has been described previously (11). The fected v-Src, oncogenic H-Ras, and vector NIH 3T3 cell lines have been pLucTKS3
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