title: XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A.
abstract: OBJECTIVE
  XPO1 inhibitors have shown promise for cancer treatment, and yet the underlying mechanisms for the antitumor effects are not well understood. In this study, we explored the usefulness of selective inhibitors of nuclear export (SINE) compounds that are specific inhibitors of XPO1.
  
  
  METHODS
  We used proteomic analysis in XPO1 inhibitor-treated ovarian cancer cell lines and examined antitumor effects in ovarian and breast cancer mouse models. We also studied the effects of XPO1 inhibitor in combination with chemotherapeutic agents.
  
  
  RESULTS
  XPO1 inhibitor treatment substantially increased the percentage of apoptotic cells (60%) after 72 hours of incubation. XPO1 inhibitor promoted the accumulation of eIF5A in mitochondria, leading to cancer cell death. Topotecan showed the greatest synergistic effect with XPO1 inhibitor. XPO1 inhibitors prevented the translocation of IGF2BP1 from the nucleus to the cytoplasm, thereby permitting the localization of eIF5A in the mitochondria. This process was p53, RB, and FOXO independent. Significant antitumor effects were observed with XPO1 inhibitor monotherapy in orthotopic ovarian (P < 0.001) and breast (P < 0.001) cancer mouse models, with a further decrease in tumor burden observed in combination with topotecan or paclitaxel (P < 0.05). This mitochondrial accumulation of eIF5A was highly dependent on the cytoplasmic IGF2BP1 levels.
  
  
  CONCLUSIONS
  We have unveiled a new understanding of the role of eIF5A and IGF2BP1 in XPO1 inhibitor-mediated cell death and support their clinical development for the treatment of ovarian and other cancers. Our data also ascertain the combinations of XPO1 inhibitors with specific chemotherapy drugs for therapeutic trials.
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Takahito
authors: T
authors: Miyake
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Sunila
authors: S
authors: Pradeep
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Sherry Y
authors: SY
authors: Wu
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Rajesha
authors: R
authors: Rupaimoole
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Behrouz
authors: B
authors: Zand
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Yunfei
authors: Y
authors: Wen
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Kshipra M
authors: KM
authors: Gharpure
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Archana S
authors: AS
authors: Nagaraja
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Wei
authors: W
authors: Hu
authors: Department of Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Min Soon
authors: MS
authors: Cho
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Heather J
authors: HJ
authors: Dalton
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Rebecca A
authors: RA
authors: Previs
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Morgan L
authors: ML
authors: Taylor
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Takeshi
authors: T
authors: Hisamatsu
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Yu
authors: Y
authors: Kang
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Tao
authors: T
authors: Liu
authors: Karyopharm Therapeutics Inc., Natick, Massachusetts.
authors: Sharon
authors: S
authors: Shacham
authors: Karyopharm Therapeutics Inc., Natick, Massachusetts.
authors: Dilara
authors: D
authors: McCauley
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: David H
authors: DH
authors: Hawke
authors: Department of Biochemistry and Molecular Biology, NHLBI Proteomics Center, The University of Texas Medical Branch, Galveston, Texas.
authors: John E
authors: JE
authors: Wiktorowicz
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Robert L
authors: RL
authors: Coleman
authors: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas. asood@mdanderson.org.
authors: Anil K
authors: AK
authors: Sood
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D015180:Electrophoresis, Gel, Two-Dimensional; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010448:Peptide Initiation Factors / Q000378:metabolism*; D040901:Proteomics; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000097574:Eukaryotic Translation Initiation Factor 5A; D000097606:Exportin 1 Protein
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D028884:Karyopherins; D010448:Peptide Initiation Factors; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000097574:Eukaryotic Translation Initiation Factor 5A; D000097606:Exportin 1 Protein