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Regulation of Vinca Alkaloid-Induced Apoptosis by NF-KB/IKB Pathway in Human Tumor Cells

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Regulation of Vinca Alkaloid-Induced Apoptosis by NF-KB/IKB Pathway in Human Tumor Cells Molecular Cancer Therapeutics 271 Regulation of Vinca alkaloid-induced apoptosis by NF-KB/IKB pathway in human tumor cells 1 1,2 2 Yi Huang, Yong Fang, Jinmin Wu, alkaloids induce the destabilization of polymerized tubulin Jennifer M. Dziadyk,1 Xueming Zhu,1 by blocking the region involved in tubulin dimer attach- Meihua Sui,1 and Weimin Fan1,2 ment, thus preventing polymerization of microtubules (2). 1 It has generally been believed that the antitumor effects of Department of Pathology and Laboratory Medicine, Medical Vinca alkaloids mainly depend on interference with the University of South Carolina, Charleston, SC and 2 Department of Oncology, Sir Run Run Shaw Hospital, Zhejiang University School normal function of microtubules and blockage of cell cycle of Medicine, Hangzhou, China progression in the G2-M phase. In recent years, several laboratories demonstrated that, at clinically relevant con- centrations, Vinca alkaloids are able to induce apoptotic cell Abstract death in several solid tumor cells (2, 3). Previous studies have revealed that glucocorticoids Antimicrotubule Vinca alkaloids, such as vinblastine and could selectively inhibit paclitaxel-induced apoptotic cell vincristine, interfere with the dynamics of microtubules death but did not affect the ability of paclitaxel to induce and have shown significant cell killing activity in a variety microtubule bundling and mitotic arrest (4, 5). This of tumor cells through induction of apoptosis. The mech- phenomenon suggested that antimicrotubule agent- anism by which Vinca alkaloids induce apoptosis is not induced apoptosis might take place via a separate pathway entirely clear. In this study, we found that glucocorticoids independent of cell cycle arrest. Further studies demon- inhibit Vinca alkaloid-induced apoptosis without affecting strated that paclitaxel and glucocorticoids possess opposite G -M arrest in human breast cancer BCap37 cells and 2 regulatory effects on InBa degradation and activation of human epidermoid tumor KB cells, suggesting that Vinca nuclear factor-nB (NF-nB; Ref. 6). NF-nB, a member of Rel alkaloid-induced apoptosis may occur via a pathway transcription factor family, and its specific intracellular independent of cell cycle arrest. Further analyses indicated inhibitor, InBa, participate in the mediation or regulation of that Vinca alkaloids cause significant degradation of many biological processes including inflammation, im- IKBA, which in turn results in nuclear factor-KB (NF-KB) mune response, cell proliferation, and apoptotic cell death activation. Transfection of antisense IKBA in BCap37 cells (7, 8). NF-nB normally resides in the cytoplasm as an sensitizes Vinca alkaloid-induced apoptosis. Moreover, inactivated form by forming a complex with its inhibitory in vitro kinase assays show that the activity of IKBki- protein InBa. On certain stimuli, InBa is rapidly phosphor- nase (IKK) was activated by Vinca alkaloids and was not ylated and degraded, allowing NF-nB to translocate to the affected by glucocorticoids. Stable transfection of domi- nucleus, where it participates in transcriptional regulation nant-negative deletional mutant IKBA, which is insensitive of numerous genes (8, 9). A key player in this cascade of to IKK-mediated phosphorylation and degradation, re- events is the InB kinase complex (IKKa and IKKh), which is sulted in the inhibition of Vinca alkaloid-induced NF-KB responsible for the phosphorylation and degradation of activation and reduced sensitivity of tumor cells to Vinca InBa (10). In recent years, increasing evidence indicates that alkaloid-induced apoptosis. These findings suggest that activation of NF-nB plays an important role in coordinating the NF-KB/IKB signaling pathway may contribute to the the control of apoptotic cell death, which either promotes or mediation of Vinca alkaloid-induced apoptosis in human inhibits apoptosis, depending on different apoptotic stim- tumor cells. [Mol Cancer Ther. 2004;3(3):271–277] ulus and cell types (9, 11–15). In this study, through characterization of the inhibitory Introduction effect of glucocorticoids on vinblastine- and vincristine- The Vinca alkaloid antimicrotubule agents, including induced apoptosis in human breast cancer BCap37 cells vinblastine and vincristine, have been widely used as and human epidermoid tumor KB cells, we obtained clinical anticancer agents for the treatment of leukemia, evidence that Vinca alkaloids cause the degradation of lymphomas, and some solid tumors (1). Unlike other InBa, which in turn promotes nuclear translocation and classes of antimicrotubule agents such as taxanes, Vinca activation of NF-nB. We also found that glucocorticoids inhibit Vinca alkaloid-induced apoptosis via antagonizing the ability of Vinca alkaloids in the activation of NF-nB. n n Received 8/12/03; revised 11/19/03; accepted 12/9/03. These findings suggest that the NF- B/I Ba signaling Grant support: NIH grants CA 92880 and CA 82440 (W. Fan). pathway plays an important role in the mediation of Vinca The costs of publication of this article were defrayed in part by the alkaloid-induced tumor cell apoptosis. payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Materials and Methods Requests for Reprints: Weimin Fan, Department of Pathology and Drugs and Cell Culture Laboratory Medicine, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425. Phone: (843) 792-5108; Vinblastine and vincristine were purchased from Sigma Fax: (843) 792-0368. E-mail: [email protected] Chemical Co. (St. Louis, MO) and dissolved in 100% DMSO Downloaded from mct.aacrjournals.org on September 24, 2021. © 2004 American Association for Cancer Research. 272 NF-nB/InB Mediates Vinca Alkaloid-Induced Apoptosis to make a stock solution with various concentrations. vinblastine or vincristine with or without TA treatment. Triamcinolone acetonide (TA) was also purchased from After 48 h of culture, cells were harvested by trypsinization Sigma Chemical and dissolved in 100% ethanol as 10À2 to and washed with PBS twice. About 5–10 Â 104 cells were À5 10 M stock solution. Wild-type breast tumor BCap37 cells, used for cytospin preparation. Slides were air-dried and stable BCap37 cells transfected with antisense InBa (6) and fixed in methanol for 5 min prior to Wright-Giemsa n mutant I Ba (16), and human epidermoid tumor KB cells staining. The DNA contents of G2-M phase of cells were were cultured in RPMI 1640 (Mediatech, Herndon, VA) counted under bright-field microscopy. Data presented supplemented with 10% fetal bovine serum and 1% represent three independent experiments. penicillin/streptomycin (Hyclone Laboratories, Logan, UT). MTT Assays Preparation of Glutathione S-Transferase-IjBa Fusion Growth inhibition was assessed by using MTT assays as Protein described previously (16). Briefly, 2 Â 105 cells/well were pGEX-InBa fusion protein expression vectors were con- plated in 96-well dishes and treated with the various drug structed by subcloning InBa cDNA restriction enzyme regimes for the indicated times. All of the experiments were fragments from pCR2.1-InBa vectors. Glutathione S-trans- plated in triplicate and the results of assays were presented ferase (GST)-InBa fusion proteins were purified from as means F SD. n Escherichia coli cells transformed with pGEX-I Ba expres- Immunoprecipitation and IKK Assays sion vectors by using glutathione-agarose affinity chroma- Cells were washed twice in PBS buffer and resuspended tography (Amersham Biosciences, Piscataway, NJ). in 500 Al of immunoprecipitation lysis buffer [50 mM Tris- Determination of Internucleosomal DNA HCl (pH 7.6), 150 mM NaCl, 10% glycerol, 1% NP40, 5 mM Fragmentation EDTA, 1 mM DTT, 100 mM NaF, 2 mM sodium After incubation with the various concentration of pyrophosphate, 2 mM sodium orthovanadate, 1 mM f 6 drug, 1 Â 10 cells were harvested and suspended in phenylmethylsulfonyl fluoride (PMSF), 10 Ag/ml of lysis buffer [5 mM Tris-HCl (pH 8.0), 20 mM EDTA, and aprotinin, and leupeptin] and stored on ice for 20 min 0.5% (v/v) Triton X-100] for 20 min on ice. The re- before centrifugation (14,000 Â g,20min,4jC). IKK com- maining steps for DNA fragmentation were performed plex was immunoprecipitated by incubation for 2 h at 4jC as described previously (6). DNA samples were analyzed with IKKa rabbit polyclonal antibodies (Santa Cruz Bio- by electrophoresis on a 1.2% agarose gel containing technology) bound to protein A-Sepharose (Pharmacia/ ethidium bromide (0.2 Ag/ml) and visualized under UV Biotech). The immunoprecipitates were washed twice with illumination. immunoprecipitation buffer and twice with kinase buff- Western Blotting er [20 mM HEPES (pH 7.4), 20 mM h-glycerophosphate, After cells were treated with the various concentrations 20 mM MgCl2,2mM DTT, and 0.1 mM sodium orthovana- of drugs, cellular proteins were isolated and fractionated date]. The kinase assays were initiated by the addition on a 12.5% SDS-PAGE gel and transferred to polyvinyli- of GST-InBa fusion protein (1 mg) and [g-32P] ATP dene difluoride (PVDF) membranes using the methods (10 Ci/mmol). Reaction mixtures were incubated for as described previously (6). The membranes were incu- 30 min at 30jC and stopped by the addition of 2Â SDS- bated with anti-InBa or anti-IKKa primary antibodies PAGE sample buffer. The phosphorylation of the InBa (1:2000; Santa Cruz Biotechnology, Santa Cruz, CA). The proteinswasexaminedbySDS-PAGEfollowedby membranes were
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