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XPO1 (CRM1) Inhibition Represses STAT3 Activation to Drive a Survivin-Dependent Oncogenic Switch in Triple-Negative Breast Cancer

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XPO1 (CRM1) Inhibition Represses STAT3 Activation to Drive a Survivin-Dependent Oncogenic Switch in Triple-Negative Breast Cancer Published OnlineFirst January 15, 2014; DOI: 10.1158/1535-7163.MCT-13-0416 Molecular Cancer Cancer Biology and Signal Transduction Therapeutics XPO1 (CRM1) Inhibition Represses STAT3 Activation to Drive a Survivin-Dependent Oncogenic Switch in Triple-Negative Breast Cancer Yan Cheng1, Michael P. Holloway1, Kevin Nguyen1, Dilara McCauley2, Yosef Landesman2, Michael G. Kauffman2, Sharon Shacham2, and Rachel A. Altura1 Abstract Inhibition of XPO1 (CRM1)-mediated nuclear export of multiple tumor suppressor proteins has been proposed as a novel cancer therapeutic strategy to turn off oncogenic signals and enhance tumor suppression. Survivin is a multifunctional protein with oncogenic properties when expressed in the cytoplasm that requires the XPO1–RanGTP complex for its nuclear export. We investigated the antitumor mechanisms of the drug-like selective inhibitors of nuclear export (SINE) XPO1 antagonists KPT-185, KPT-251 KPT-276, and KPT-330 in estrogen receptor–positive and triple-negative breast cancer (TNBC) cell lines and xenograft models of human breast tumors. KPT compounds significantly inhibited breast cancer cell growth and induced tumor cell death, both in vitro and in vivo. These drugs initially promoted survivin accumulation within tumor cell nuclei. However, their major in vitro effect was to decrease survivin cytoplasmic protein levels, correlating with the onset of apoptosis. XPO1 inhibition repressed Survivin transcription by inhibiting CREB-binding protein- mediated STAT3 acetylation, and blocking STAT3 binding to the Survivin promoter. In addition, caspase-3 was activated to cleave survivin, rendering it unavailable to bind X-linked inhibitor of apoptosis protein and block the caspase cascade. Collectively, these data demonstrate that XPO1 inhibition by SINE compounds represses STAT3 transactivation to block the selective oncogenic properties of survivin and supports their clinical use in TNBC. Mol Cancer Ther; 13(3); 675–86. Ó2014 AACR. Introduction they are exported out of the nucleus. Therefore, inhibiting XPO1, one of the seven nuclear exportin proteins XPO1, leading to forced nuclear localization, accumula- required for all mammalian cells, shuttles approximately tion, and activation of tumor suppressor proteins, is 220 diverse proteins and some RNAs from the nucleus to considered a potential therapeutic target for anticancer the cytoplasm (1–4). XPO1 interacts with cargo proteins drug development. through a nuclear export sequence (NES) that is depen- Survivin is a multifunctional protein with its major dent on the small GTPase protein Ran in its GTP-bound oncogenic property being inhibition of caspase-depen- form, which binds to XPO1 together with export cargos dent apoptosis that it accomplishes, in part, by stabilizing (2). NES-containing cargo proteins include multiple tran- X-linked inhibitor of apoptosis (XIAP) in the cytoplasm of scription factors and tumor suppressor proteins that play tumor cells (9). Survivin is highly expressed in breast key roles in the growth and survival of cancer cells. tumor cells and is one of the genes profiled on OncoDx Interestingly, XPO1 is the sole nuclear export protein for and Mammoprint as a predictor of clinical response to the major tumor suppressor proteins (e.g., p53; ref. 5), therapy (10). Survivin export from the nucleus to the STAT3; ref. 6), survivin; ref. 7), FOXO3; ref. 8). Many of cytoplasm is mediated by the XPO1–Ran-GTP complex these proteins lose their tumor suppressor function when (7, 11); cytoplasmic localization is required for survivin’s antiapoptotic and tumor-promoting functions (12–14). Disruption of the survivin NES leads to enhanced sus- Authors' Affiliations: 1Division of Hematology-Oncology, Department of ceptibility to anticancer treatments (12, 14). One mecha- Pediatrics, The Warren Alpert Medical School at Brown University and Rhode Island Hospital, Providence, Rhode Island; and 2Karyopharm Ther- nism of targeting survivin’s selective cytoplasmic func- apeutics Inc., Natick, Massachusetts tion without affecting its antitumor nuclear effects could Note: Supplementary data for this article are available at Molecular Cancer be to inhibit its cytoplasmic export. Therapeutics Online (http://mct.aacrjournals.org/). STAT3 is a member of the Janus-activated kinase Corresponding Author: Rachel A. Altura, Department of Pediatrics, Rhode (JAK)/STAT that is constitutively activated in multiple Island Hospital, 593 Eddy Street, Providence, RI 02903. Phone: 401-444- cancer types (15), including triple-negative breast cancer 5171; Fax: 401-444-8845; E-mail: [email protected] (TNBC). STAT3 activation in these tumors leads to doi: 10.1158/1535-7163.MCT-13-0416 increased expression of antiapoptotic proteins, including Ó2014 American Association for Cancer Research. survivin (16, 17), and other proteins to enhance cell www.aacrjournals.org 675 Downloaded from mct.aacrjournals.org on October 3, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst January 15, 2014; DOI: 10.1158/1535-7163.MCT-13-0416 Cheng et al. proliferation, induce angiogenesis, and suppress immune inhibitors (KPT-185cis, KPT-185trans, KPT-276, KPT- responses. Thus, STAT3 is a potential high-yield target for 330) were obtained from Karyopharm Therapeutics, Inc. drug development to treat TNBC for which there are no A 10-mmol/L stock solution dissolved in dimethyl sulf- currently approved molecular therapies. Although sev- oxide was diluted in medium to the final concentrations eral small-molecule STAT3 inhibitors have been reported indicated. To inhibit protein translation, cells were treated (18–20), thus far none are in clinical trials due to pharma- with 20 mg/mL cyclohexamide (CHX; Sigma-Aldrich). To cokinetic and other problems. Interestingly, STAT3 has inhibit proteasome-mediated degradation, cells were several NES elements through which it binds to XPO1 for treated with 2 mmol/L MG132 (SelleckBio.com) for 18 its nuclear export (21). hours or 40 mmol/L MG132 for 6 hours. To inhibit cas- Leptomycin B (LMB) was the first natural XPO1 inhib- pase-3 and caspase-9, cells were treated with 20 mmol/L of itor discovered that was shown to be a potent anticancer inhibitors for 4 hours. Of note, 6Â MYC-survivin was a gift agent (22). This agent failed in early clinical trials due to from H. Cheung (University of Ottawa). Cells were trans- off-target side effects predictable from animal toxicity fected with siRNA to XPO1 (Ambion/Invitrogen), survi- testing, prompting the development of more selective and vin (Cell Signaling Technology), XIAP (Thermo Scientific less toxic XPO1 inhibitors (23). The recent crystal structure Dharmacon), or control (Thermo Scientific Dharmacon). of LMB and XPO1 shows that LMB binds covalently to Cys-528 in the XPO1 NES-binding groove, occupying the Cell viability and apoptosis assays majority of the groove and undergoing hydrolysis by Cells were seeded at a density of 5,000 cells/well then XPO1 (24). Newer small-molecule, selective inhibitors of treated at the doses indicated. Seventy hours later, cells nuclear export (SINE) XPO1 antagonists developed by were incubated with CellTiter 96 Aqueous One Solution Karyopharm Therapeutics, Inc. bind similarly in the NES Reagent (Promega), and viability was assessed using a groove; however, due to their smaller size, these mole- Synergy Mx Monochromator (BioTek Instrument Inc.). cules occupy less space and are more specific for XPO1, Flow cytometry-based apoptosis assays were performed with no detectable binding to other proteins (24). X-ray with the Annexin V-FITC Apoptosis Kit (Biovision), fol- crystal structures of SINEs bound to XPO1 have been lowing the manufacturer’s instructions. Multiwell plate published and confirm covalent modification of Cys528 apoptosis assays were performed with the Annexin V (24). SINEs have been demonstrated to reduce tumor FITC Assay Kit (Cayman Chemical). growth with good tolerability in several preclinical mod- els of hematologic cancers and solid tumors (25, 26). The IC50 determination exact molecular mechanism of their antitumor effects in Subconfluent cultures were grown in 96-well plates and different cancer subtypes is not yet well defined. treated with KPT compounds for 72 hours before perform- We sought to characterize the effects of XPO1 inhibition ing MTT assays with CellTiter 96 AQueous One Solution on survivin using a breast cancer model and the SINE Cell Proliferation Assay (Promega). Data were graphed compounds. In vitro and in vivo assays demonstrated that and analyzed using Kaleidagraph software (Synergy Soft- these drugs potently inhibit breast cancer growth by ware). Assay values obtained in triplicate were used to blocking proliferation and enhancing cell death path- derive the IC50 by curve fitting to the Hill equation. ways, as demonstrated for other tumor types. Important- ly, here we show that these compounds can dramatically Subcellular fractionation, immunoprecipitation, repress Survivin transcription by blocking STAT3 trans- Western blot analysis, and tricine-SDS-PAGE activation and that they enhance survivin degradation Subcellular fractionation was performed as previously through cleavage by caspase-3. These results identify described (27). Immunocomplexes were resolved by SDS- survivin- and STAT3-dependent mechanisms for the PAGE. Tricine-SDS-PAGE was carried out as described XPO1 inhibitors that may explain their in vivo antitumor (28). Anti-XPO1 (H-300): sc-5595, anti-survivin (D-8), anti- effects. We also note that XPO1 inhibitors force
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