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Cucurbitacin Q: a Selective STAT3 Activation Inhibitor with Potent Antitumor Activity

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Cucurbitacin Q: a Selective STAT3 Activation Inhibitor with Potent Antitumor Activity Oncogene (2005) 24, 3236–3245 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity Jiazhi Sun1,2, Michelle A Blaskovich1,2, Richard Jove1, Sandra K Livingston1, Domenico Coppola1 and Saı¨ d M Sebti*,1 1Departments of Interdisciplinary Oncology and Biochemistry and Molecular Biology, Drug Discovery and Molecular Oncology Programs, H Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, MRC-DRDIS, Tampa, FL 33612-9497, USA Constitutive activation of the JAK/STAT3 pathway is a Introduction major contributor to oncogenesis.In the present study, structure–activity relationship (SAR) studies with five Signal transducers and activators of transcription cucurbitacin (Cuc) analogs, A, B, E, I, and Q, led to the (STATs) are a family of seven proteins (STATs 1, 2, 3, discovery of Cuc Q, which inhibits the activation of 4, 5a, 5b, and 6) unique in their ability both to transduce STAT3 but not JAK2; Cuc A which inhibits JAK2 but not extracellular signals and regulate transcription directly. STAT3 activation; and Cuc B, E, and I, which inhibit the STATs transduce extracellular signals from cytokines activation of both.Furthermore, these SAR studies such as interleukin-6 and interferons or growth factors demonstrated that conversion of the C3 carbonyl of the such as platelet-derived growth factor (PDGF) and cucurbitacins to a hydroxyl results in loss of anti-JAK2 epidermal growth factor (EGF). Upon activation of activity, whereas addition of a hydroxyl group to C11 of these receptors, STATs are recruited to the plasma the cucurbitacins results in loss of anti-STAT3 activity. membrane where they become activated via phosphor- Cuc Q inhibits selectively the activation of STAT3 and ylation of conserved tyrosine residues either directly by induces apoptosis without inhibition of JAK2, Src, Akt, receptor tyrosine kinases, for example, PDGF receptor Erk, or JNK activation.Furthermore, Cuc Q induces (PDGFR) and EGF receptor (EGFR) or by nonrecep- apoptosis more potently in human and murine tumors that tor tyrosine kinases, for example, Src and JAK. contain constitutively activated STAT3 (i.e., A549, Phosphorylated STAT proteins either homo- or hetero- MDA-MB-435, and v-Src/NIH 3T3) as compared to dimerize via reciprocal phosphotyrosine–SH2 interac- those that do not (i.e., H-Ras/NIH 3T3, MDA-MB-453, tions after which the STAT dimers translocate to the cell and NIH 3T3 cells).Finally, in a nude mouse tumor nucleus where they bind DNA at STAT-specific binding xenograft model, Cuc Q, but not Cuc A, suppresses tumor sites. growth indicating that JAK2 inhibition is not sufficient to In normal cells STAT proteins have been identified as inhibit tumor growth and suggesting that the ability of important regulators of diverse physiological functions Cuc Q to inhibit tumor growth is related to its anti- such as immune response, inflammation, proliferation, STAT3 activity.These studies further validate STAT3 as differentiation, development, cell survival, and apopto- a drug discovery target and provide evidence that sis (Ihle and Kerr, 1995; Schindler and Darnell, 1995; pharmacological agents that can selectively reduce the Horvath and Darnell, 1997; Stark et al., 1998). STAT P-STAT3 levels in human cancer cells result in tumor signaling is tightly regulated in normal cells, either apoptosis and growth inhibition. through inhibition of upstream signaling proteins (e.g., Oncogene (2005) 24, 3236–3245. doi:10.1038/sj.onc.1208470 internalization of receptors) or negative regulators of Published online 21 February 2005 Src and JAK proteins, such as SOCS proteins, and Src family and JAK phosphatases (e.g., CD45 and SHP-2) Keywords: STAT3; apoptosis; antitumor activity; (Irie-Sasaki et al., 2001; Myers et al., 2001; Lefebvre cucurbitacins; JAK2 et al., 2003; Lehmann et al., 2003). STAT proteins have been demonstrated to be directly negatively regulated by SOCs proteins, by protein inhibitors of activated STATs (PIAS ), by SHP phosphatases, and recent evidence has shown both Grb2 and GRIM-19 to be novel regulators of STAT3 activation (Lufei et al., 2003; Zhang et al., *Correspondence: SM Sebti, Drug Discovery Program, H. Lee Moffitt 2003; Wormald and Hilton, 2004). However, in both Cancer Center & Research Institute, 12902 Magnolia Drive, MRC- tumor cells and tissues, disregulation and constitutive DRDIS, Tampa, FL 33612-9497, USA; activation of STATs, especially STAT3 and STAT5, E-mail: sebti@moffitt.usf.edu 2These two authors contributed equally to this work have been demonstrated to be important to the Received 14 October 2004; revised 14 December 2004; accepted 14 proliferation and antiapoptotic activity of tumor cells December 2004; published online 21 February 2005 (Bowman and Jove, 1999; Turkson and Jove, 2000). Inhibition of STAT3 activation with cucurbitacin Q J Sun et al 3237 STATs have been shown to play active roles at all In this paper, structure–activity relationship (SAR) levels of tumorigenesis. STATs are responsible for studies have identified cucurbitacin Q (Cuc Q) as generating proproliferative signals (e.g., Cyclin D1, an inhibitor of the activation of STAT3 but not survivin; Sinibaldi et al., 2000; Aoki et al., 2003) JAK2. In contrast, Cuc A was found to be an inhibitor and have been shown to upregulate antiapoptotic of JAK2 but not STAT3 activation. Furthermore, Cuc proteins (e.g., Bcl-XL, Bcl-2; Catlett-Falcone et al., Q but not A induces apoptosis and inhibits human 1999). In addition, STAT3 has been demonstrated tumor growth in mice. Finally, Cuc Q induces apoptosis to upregulate VEGF expression, which is necessary selectively in tumors that contain constitutively acti- for angiogenesis and the maintenance of tumor vascu- vated STAT3 but not in those tumors without activated lature (Niu et al., 2002b). Finally, STAT3 has been STAT3. implicated in the inhibition of immune responses to tumor growth by blocking expression of proinflamma- tory factors (Wang et al., 2004). Unregulated activation Results of STAT3 and STAT5 has been demonstrated in a variety of tumor types, including breast carcinoma, Cuc Q selectively suppresses STAT3 but not JAK2 prostate cancer, melanoma, multiple myeloma, and activation in A549 cells leukemia among others (Shuai et al., 1996; Garcia et al., 1997, 2001; Catlett-Falcone et al., 1999; Mora Having previously identified cucurbitacin I (JSI-124) as et al., 2002; Niu et al., 2002a). Various genetic a potent inhibitor of activation of both JAK2 and alterations can lead to constitutive activation of either STAT3 prompted us to carry out SAR studies to STAT3 or STAT5 (e.g., overexpression of EGFR and identify agents that are selective for inhibiting the ErbB2; Fernandes et al., 1999; Berclaz et al., 2001). activation of either JAK2 or STAT3. To this end, Autocrine and paracrine production of IL-6 results in A549 cells (a human non-small-cell lung carcinoma line) activation of STAT3 in prostate cancer and multiple were treated with either vehicle or cucurbitacin analogs myeloma (Catlett-Falcone et al., 1999; Mora et al., A, B, E, I, or Q (10 mM) for 4 h and the cell lysates 2002), while the oncogene BCR-Abl has been demon- processed for Western blotting with antiphosphotyro- strated to act through constitutive tyrosine phosphor- sine STAT3 (Y705) antibody or antiphosphotyrosine ylation of STAT5 in chronic myelogenous leukemia JAK2 (Y1007, Y1008) antibody as described under (Shuai et al., 1996). Various other tyrosine kinases, for Materials and methods. Figure 1a shows that Cuc Q example, TEL-JAK2, v-Src, and c-Kit, may require suppressed the levels of P-STAT3 but had no effect on activation of downstream signaling pathways including those of P-JAK2. In contrast, Cuc A suppressed the STAT3 and STAT5 (Yu et al., 1995; Cao et al., 1996; levels of P-JAK2 but had no effect on those of P- Ning et al., 2001; Spiekermann et al., 2002; Paner et al., STAT3. Cuc B, E, and I inhibited both P-STAT3 and P- 2003). JAK2 levels (Figure 1a). The fact that Cuc B, E, I, and On the basis of the importance of STAT3 in tumor Q, but not A, suppressed P-STAT3 levels in A549 cells progression and survival, we and others recently have indicates that addition of a single hydroxyl to carbon 11 begun to focus on STAT3 as a viable molecular target of the cucurbitacin pharmacophore results in loss of for cancer chemotherapeutics (Turkson and Jove, 2000). anti-STAT3 activity (Figure 1a; compare Cuc A to B). Several different approaches can be taken for the Similarly, the ability of Cuc A, B, E, and I, but not Q, to inhibition of the STAT signaling pathway: targeting suppress P-JAK2 levels indicates that simple conversion receptor–ligand interactions; inhibition of upstream of the carbon 3 carbonyl in the cucurbitacins to a STAT-activating receptor tyrosine kinases and nonre- hydroxyl results in loss of anti-JAK2 activity (Figure 1a; ceptor tyrosine kinases; activation of STAT phospha- compare cucurbitacin Q to B). tases and other negative regulators of STATs; and To confirm that Cuc Q decreases phosphotyrosine inhibition of STAT dimerization, nuclear translocation, levels of STAT3 without affecting total STAT3 levels, DNA binding, or DNA transcription. Studies with we treated A549 cells with either vehicle control or Cuc antisense, gene therapy, and RNA interference (siRNA) Q (10 mM) for 4 h, immunoprecipitated the lysates (Niu et al., 1999, 2002b; Konnikova et al., 2003) have against whole STAT3, then blotted with both P-STAT3 demonstrated that inhibition of STAT3 signaling and STAT3 antibodies as described under Materials and suppresses tumor growth and induces apoptosis in cell methods. Figure 1b shows that Cuc Q treatment lines and mouse models, validating STAT3 as a target suppressed P-STAT3 without affecting total STAT3 for molecular intervention. Recently, pharmacological levels.
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