title: XPO1 (CRM1) inhibition represses STAT3 activation to drive a survivin-dependent oncogenic switch in triple-negative breast cancer.
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.
authors.affiliation: Corresponding Author: Rachel A. Altura, Department of Pediatrics, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. rachel_altura@brown.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Michael P
authors.initials: MP
authors.lastname: Holloway
authors.forename: Kevin
authors.initials: K
authors.lastname: Nguyen
authors.forename: Dilara
authors.initials: D
authors.lastname: McCauley
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kauffman
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Altura
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D000077022:Survivin; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000097606:Exportin 1 Protein
chemical_list: D053148:Caspase 3; D051034:Inhibitor of Apoptosis Proteins; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D050796:STAT3 Transcription Factor; D000077022:Survivin; D000097606:Exportin 1 Protein; C107489:BIRC5 protein, human; C494086:STAT3 protein, human