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Ursolic Acid Inhibits STAT3 Activation Pathway Leading to Suppression of Proliferation and Chemosensitization of Human Multiple Myeloma Cells

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Ursolic Acid Inhibits STAT3 Activation Pathway Leading to Suppression of Proliferation and Chemosensitization of Human Multiple Myeloma Cells Ursolic Acid Inhibits STAT3 Activation Pathway Leading to Suppression of Proliferation and Chemosensitization of Human Multiple Myeloma Cells Ashutosh K. Pathak,1 Manisha Bhutani,1 Asha S. Nair,1 Kwang Seok Ahn,1 Arup Chakraborty,2 Humam Kadara,3 Sushovan Guha,4 Gautam Sethi,1 and Bharat B. Aggarwal1 1Cytokine Research Laboratory, 2Department of Experimental Therapeutics, 3Department of Thoracic/Head andNeck Medical Oncology, and 4Department of Gastrointestinal Medicine and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, Texas Abstract significantly potentiated the apoptotic effects of The activation of signal transducers and activators of thalidomide and bortezomib in multiple myeloma cells. transcription 3 (STAT3) has been linked with the Overall, these results suggest that ursolic acid is a novel proliferation of a variety of human cancer cells, blocker of STAT3 activation that may have a potential including multiple myeloma. Agents that can suppress in prevention and treatment of multiple myeloma and STAT3 activation have potential for prevention and other cancers. (Mol Cancer Res 2007;5(9):943–55) treatment of cancer. In the present report, we tested an agent, ursolic acid, found in basil, apples, prunes, and Introduction cranberries, for its ability to suppress STAT3 activation. Signal transducer and activator of transcription (STAT) We found that ursolic acid, a pentacyclic triterpenoid, proteins have been shown to play an important role in tumor inhibited both constitutive and interleukin-6–inducible cell survival and proliferation (1). One STAT family member, STAT3 activation in a dose- and time-dependent STAT3, is often constitutively active in many human cancer manner in multiple myeloma cells. The suppression cells including multiple myeloma, leukemia, lymphoma, and was mediated through the inhibition of activation of solid tumors (2, 3). STAT3 can also be activated by certain upstream kinases c-Src, Janus-activated kinase 1, interleukins [e.g., interleukin-6 (IL-6)] and growth factors Janus-activated kinase 2, and extracellular signal– (e.g., epidermal growth factor). On activation, STAT3 under- regulated kinase 1/2. Vanadate treatment reversed the goes phosphorylation-induced homodimerization, leading to ursolic acid–induced down-regulation of STAT3, nuclear translocation, DNA binding, and subsequent gene suggesting the involvement of a tyrosine phosphatase. transcription. The phosphorylation is mediated through the Indeed, we found that ursolic acid induced the activation of nonreceptor protein tyrosine kinases called Janus- expression of tyrosine phosphatase SHP-1 protein activated kinases (JAK). JAK1, JAK2, JAK3, and TYK2 have and mRNA. Moreover, knockdown of SHP-1 by small been implicated in the activation of STAT3 (4, 5). In addition, interfering RNA suppressed the induction of SHP-1 and the role of c-Src kinase has been shown in STAT3 phos- reversed the inhibition of STAT3 activation, thereby phorylation (6). Besides tyrosine phosphorylation, there is indicating the critical role of SHP-1 in the action of this evidence that STAT3 can undergo serine phosphorylation as triterpene. Ursolic acid down-regulated the expression well, which is mediated through the activation of kinases of of STAT3-regulated gene products such as cyclin D1, the mitogen-activated protein kinase family (7). Bcl-2, Bcl-xL, survivin, Mcl-1, and vascular endothelial The major phosphorylation sites in STAT3 include tyrosine growth factor. Finally, ursolic acid inhibited proliferation and serine residues at positions 705 and 727, respectively, and induced apoptosis and the accumulation of cells located in the transactivation domain. The activation of STAT3 in G1-G0 phase of cell cycle. This triterpenoid also results in expression of numerous gene products required for tumor cell survival (e.g., survivin, Bcl-xL, Bcl-2, and Mcl-1), proliferation (e.g., cyclin D1), and angiogenesis [e.g., vascular endothelial growth factor (VEGF); ref. 8]. Thus, agents that Received 10/17/06; revised 5/23/07; accepted 5/23/07. Grant support: Clayton Foundation for Research and NIH P01 grant CA91844 suppress STAT3 activation have a potential in prevention and on lung chemoprevention (B.B. Aggarwal) and NIH core grant 5P30 CA016672- therapy of cancer (9, 10). 32 for flow cytometric analysis. One potential source of STAT3 inhibitors is natural dietary The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in components. Numerous animal studies and epidemiologic accordance with 18 U.S.C. Section 1734 solely to indicate this fact. studies in humans suggest that fruits and vegetables can Note: Dr. B.B. Aggarwal is a Ransom Horne, Jr., Professor of Cancer Research. prevent cancer (11). We describe here the identification of a Requests for reprints: Bharat B. Aggarwal, Department of Experimental Therapeutics/Ransom Horne, Jr., M. D. Anderson Cancer Center, 1515 Holcombe compound derived from rosemary (Rosemarinus officinalis), Boulevard, Box 143, Houston, TX 77030. Phone: 713-792-3503/6459; Fax: 713- apples (Malus domestica), cranberries (Vaccinium macrocar- 794-1613. E-mail: [email protected] Copyright D 2007 American Association for Cancer Research. pon), makino (Perilla frutescens), pears (Pyrus pyrifolia), doi:10.1158/1541-7786.MCR-06-0348 prunes (Prunus domestica), bearberries (Arctostaphylos Mol Cancer Res 2007;5(9). September 2007 943 Downloaded from mcr.aacrjournals.org on September 25, 2021. © 2007 American Association for Cancer Research. 944 Pathak et al. alpina), loquat (Eriobotrya japonica), scotch heather (Calluna cells were incubated with different concentrations of ursolic vulgaris), basil (Ocimum sanctum), and jamun (Eugenia acid for 4 h and whole-cell extracts were prepared and jumbolana; ref. 12), called ursolic acid, which has a potential examined for phosphorylated STAT3 by Western blot analysis in prevention of cancer. Ursolic acid is a pentacyclic with antibody that recognizes STAT3 phosphorylated at Tyr705. triterpenoid that has been shown to suppress the growth of As shown in Fig. 1E, ursolic acid inhibited the constitutive various hematopoietic tumors (13, 14), inhibit tumor promotion activation of STAT3 in U266 cells in a dose-dependent manner, (15, 16), and inhibit tumor angiogenesis (17). We have recently with maximum inhibition occurring at 50 to 100 Amol/L. shown that ursolic acid is a potent inhibitor of nuclear factor-nB Ursolic acid had no effect on the expression of STAT3 protein (NF-nB) activation pathway (18), which is activated by inflam- (Fig. 1E, bottom). AG490 is a well-characterized inhibitor of matory agents, carcinogens, and tumor promoters. JAK2-STAT3 phosphorylation (20). Similar to ursolic acid, Because of the critical role of STAT3 in tumor cell survival, exposure of cells to 50 Amol/L of AG490 was needed to inhibit proliferation, and angiogenesis, we hypothesized that ursolic STAT3 phosphorylation (Fig. 1F). acid mediates its effects, in part, through suppression of the We also determined the incubation time with ursolic acid STAT3 pathway. We tested this hypothesis in multiple myeloma required for suppression of STAT3 activation in U266 cells. cells. In our experiments, ursolic acid indeed suppressed both As shown in Fig. 1G, the inhibition was time dependent, with constitutive and inducible STAT3 activation. This inhibition maximum inhibition occurring at f4 h, again with no effect on decreased cell survival and down-regulated expression of proli- the expression of STAT3 protein (Fig. 1G, bottom). In com- ferative and angiogenic gene products, leading to suppression parison, 8 h was required to suppress STAT3 activation by of proliferation, induction of apoptosis, and enhancement of AG490 (data not shown). the response to the cytotoxic effects of thalidomide (an inhibitor of tumor necrosis factor expression) and bortezomib (a protea- Effect of Ursolic Acid on STAT3 Phosphorylation Is some inhibitor; also called PS341) in multiple myeloma cells. Specific Whether ursolic acid affects the activation of other STAT3 Results proteins in U266 cells was also investigated. Under the conditions We have previously shown that ursolic acid is a potent where ursolic acid completely inhibited STAT3 phosphorylation, inhibitor of activation of NF-nB (18), a transcription factor that it altered neither the levels of constitutively phosphorylated plays a critical role in the survival and proliferation of tumor STAT5 nor the expression of STAT5 proteins (Fig. 1H). cells. The present study was undertaken to determine the effect of ursolic acid on STAT3 signaling pathway. We investigated the effect of ursolic acid on both constitutive and IL-6– Ursolic Acid Depletes Nuclear Pool of STAT3 in Multiple inducible STAT3 activation in multiple myeloma cells. We also Myeloma Cells evaluated the effect of ursolic acid on various mediators of Because nuclear translocation is central to the function of cellular proliferation, cell survival, and apoptosis. The structure transcription factors and because it is not certain whether of ursolic acid is shown in Fig. 1A. The dose and duration of phosphorylation is mandatory for nuclear transport of STAT3 ursolic acid used for STAT3 experiments had no effect on cell and its oncogenic functions (21, 22), we determined whether viability (data not shown). ursolic acid suppresses nuclear translocation of STAT3. Figure 1I clearly shows that ursolic acid inhibited the translocation
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