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Cited by 47Nuclear Structure and FunctionDrug Transport and Resistance MechanismsGastric Cancer Management and Outcomes

Targeting Nuclear Exporter Protein XPO1/CRM1 in Gastric Cancer

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Sexton, Rachel, Mahdi, Zaid, Chaudhury, Rahman, Beydoun, Rafic, Aboukameel, Amro, Khan, Husain Y., Baloglu, Erkan, Senapedis, William +5 more·2019·International Journal of Molecular Sciences
DOI 10.3390/ijms20194826PMC PMC6801932
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Abstract

Gastric cancer remains an unmet clinical problem in urgent need of newer and effective treatments. Here we show that the nuclear export protein, Exportin 1 (XPO1, chromosome region maintenance 1 or CRM1), is a promising molecular target in gastric cancer. We demonstrate significant overexpression of XPO1 in a cohort of histologically diverse gastric cancer patients with primary and metastatic disease. XPO1 RNA interference suppressed gastric cancer cell growth. Anti-tumor activity was observed with specific inhibitor of nuclear export (SINE) compounds (selinexor/XPOVIO), second-generation compound KPT-8602/eltanexor, KPT-185 and +ve control Leptomycin B in three distinct gastric cancer cell lines. SINE compounds inhibited gastric cancer cell proliferation, disrupted spheroid formation, induced apoptosis and halted cell cycle progression at the G1/S phase. Anti-tumor activity was concurrent with nuclear retention of tumor suppressor proteins and inhibition of colony formation. In combination studies, SINE compounds enhanced the efficacy of nab-paclitaxel in vitro and in vivo. More significantly, using non-coding RNA sequencing studies, we demonstrate for the first time that SINE compounds can alter the expression of non-coding RNAs (microRNAs and piwiRNAs). SINE treatment caused statistically significant downregulation of oncogenic miR-33b-3p in two distinct cell lines. These studies demonstrate the therapeutic significance of XPO1 in gastric cancer that warrants further clinical investigation.

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  • Overexpression of miR-33b-3p enhanced cell proliferation and colony formation in gastric cancer.

    “Overexpression of miR-33b-3p enhanced cell proliferation and colony formation in gastric cancer (35), indicating the oncomir function of miR-33b-3p.”

    From miR-33b-3p Acts as a Tumor Suppressor by Targeting DOCK4 in Prostate Cancer (2021) · cites this paper as [35]

    Results §2.5 reports that a miR-33b-3p mimic significantly enhanced cellular growth in two gastric cancer cell lines and affected colony formation in NCI-N87 cells. The text says colony formation was “influenced,” but does not state that it increased, so that part of the claim is not fully supported. (LLM, conf=0.86)

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  1. [3]Ajani J.A. D’Amico T.A. Almhanna K. Bentrem D.J. Chao J. Das P. Denlinger C.S. Fanta P. Farjah F. Fuchs C.S. Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology JNCCN 2016 14 1286 1312 10.6004/jnccn.2016.0137 27697982 · DOI
  2. [4]Crew K.D. Neugut A.l. Epidemiology of Gastric Cancer World J. Gastroenterol. 2006 12 354 362 10.3748/wjg.v12.i3.354 16489633 PMC4066052 · DOI
  3. [5]Salem M.E. Puccini A. Xiu J. Raghavan D. Lenz H.J. Korn W.M. Shields A.F. Philip P.A. Marshall J.L. Goldberg R.M. Comparative Molecular Analyses of Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma and Gastric Adenocarcinoma Oncologist 2018 23 1319 1327 10.1634/theoncologist.2018-0143 29866946 PMC6291329 · DOI
  4. [6]Hakkaart C. Ellison-Loschmann L. Day R. Sporle A. Koea J. Harawira P. Cheng S. Grey M. Waanga T. Pearce N. Germline CDH1 mutations are a significant contributor to the high frequency of early diffuse gastric cancer cases in New Zealand Maori Fam. Cancer 2018 18 83 90 10.1007/s10689-018-0080-8 PMC6323075 29589180 · DOI
  5. [7]Van Beek E.J.A.H. Hernandez J.M. Goldman D.A. Davis J.L. McLaughlin K. Ripley R.T. Kim T.S. Tang LH. Hechtman J.F. Zheng J. Rates of TP53 Mutation are significantly elevated in African American Patients with Gastric Cancer Ann. Surg. Oncol. 2018 25 2027 2033 10.1245/s10434-018-6502-x 29725898 PMC6644702 · DOI
  6. [8]Stade K. Ford C.S. Gunthrie C. Weis K. Exportin 1 (Crm1p) is an essential Nuclear Export Factor Cell 2017 90 1041 1050 10.1016/S0092-8674(00)80370-0 9323132 · DOI
  7. [9]Nguyen K.T. Holloway M.P. Altura R.A. The CRM1 nuclear export protein in normal development and disease Int. J. Biochem. Mol. Biol. 2012 3 137 151 22773955 PMC3388738
  8. [10]Azmi A.S. Aboukameel A. Bao B. Sarkar F.H. Philip P.A. Kauffman M. Shacham S. Mohammad R.M. Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice Gastroenterology 2013 144 447 456 10.1053/j.gastro.2012.10.036 23089203 PMC3594519 · DOI
  9. [11]Gandhi U.H. Senapedis W. Baloglu E. Unger T.J. Chari A. Vogl D. Cornell R.F. Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma Clin. Lymphoma Myeloma Leuk. 2018 18 335 345 10.1016/j.clml.2018.03.003 29610030 · DOI
  10. [12]Gupta A. Saltarski J.M. White M.A. Scaglioni P.P. Gerber D.E. Therapeutic Targeting of Nuclear Export Inhibition in Lung Cancer J. Thorac. Oncol. 2017 12 1446 1450 10.1016/j.jtho.2017.06.013 28647672 PMC5572747 · DOI
  11. [13]Chen Y. Camacho S.C. Silvers T.R. Razak A.R. Gabrail N.Y. Gerecitano J.F. Kalir E. Pereira E. Evans E.R. Ramus S.J. Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer Clin. Cancer Res. 2017 23 1552 1563 10.1158/1078-0432.CCR-16-1333 27649553 · DOI
  12. [14]Kashyap T. Argueta C. Aboukameel A. Unger T.J. Klebanov B. Mohammad R.M. Muqbil I. Azmi A.S. Drolen C. Senapedis W. Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-kB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death Oncotarget 2016 7 78883 78895 10.18632/oncotarget.12428 27713151 PMC5346685 · DOI
  13. [15]Alexander T.B. Lacayo N.J. Choi J.K. Ribeiro J.K. Pui C.H. Rubnitz J.E. Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination with Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia J. Clin. Oncol. 2016 34 4094 4101 10.1200/JCO.2016.67.5066 27507877 PMC5477824 · DOI
  14. [16]Turner J.G. Kashyap T. Dawson J.L. Gomez J. Bauer A.A. Grant S. XPO1 inhibition combination therapy with bortezomib or carfilzomib induces nuclear localization of IkBa and overcomes acquired proteasome inhibitor resistance in human multiple myeloma Oncotarget 2016 7 78896 78909 10.18632/oncotarget.12969 27806331 PMC5340237 · DOI
  15. [17]Kashyap T. Argueta C. Unger T. Klebanov B. Debler S. Senapedis W. Crochiere M.L. Lee M.S. Kauffman M. Shacham S. Selinexor reduces the expression on DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents Oncotarget 2018 9 30773 30786 10.18632/oncotarget.25637 30112106 PMC6089403 · DOI
  16. [18]Muqbil I. Aboukameel A. Elloul S. Carlson R. Senapedis W. Baloglu E. Kauffman M. Shacham S. Bhutani D. Zonder J. Anti-tumor activity of selective inhibitor of nuclear export (SINE) compounds, is enhanced in non-Hodgkin lymphoma through combination with mTOR inhibitor and dexamethasone Cancer Lett. 2016 383 309 317 10.1016/j.canlet.2016.09.016 27693556 PMC5584550 · DOI
  17. [23]XPO1 Inhibitor Approved for Multiple Myeloma Cancer Discov. 2019 10.1158/2159-8290.CD-NB2019-085 31332020 · DOI
  18. [25]Wang A.Y. Liu H. The past, present, and future of CRM1/XPO1 inhibitors Stem Cell Investig. 2019 6 6 10.21037/sci.2019.02.03 PMC6414360 30976603 · DOI
  19. [26]Lecane P.S. Kiviharju T.M. Sellers R.G. Peehl D.M. Leptomycin B stabilizes and activates p53 in primary prostatic epithelial cells and induces apoptosis in the LNCaP cell line Prostate. 2003 54 258 267 10.1002/pros.10197 12539224 · DOI
  20. [27]Bussing I. Yang J.S. Lai E.C. Grobhans H. The nuclear export receptor XPO-1 supports primary miRNA processing in C. elegans and Drosophilia EMBO J. 2010 29 1830 1839 10.1038/emboj.2010.82 20436454 PMC2885935 · DOI
  21. [28]Martinez V.D. Enfield K.S.S. Rowbotham D.A. Lam W.L. An atlas of gastric PIWI-interacting RNA transcriptomes and their utility for identifying signatures of gastric cancer recurrence Gastric. Cancer 2016 19 660 665 10.1007/s10120-015-0487-y 25779424 PMC4573768 · DOI
  22. [29]Wu K. He J. Pu W. Peng Y. The Role of Exportin-5 in MicroRNA Biogenesis and Cancer Genom. Proteom. Bioinform. 2018 16 120 126 10.1016/j.gpb.2017.09.004 29723684 PMC6112314 · DOI
  23. [30]Muqbil I. Bao B. Abou-Samra A.B. Mohammad R.M. Azmi A.S. Nuclear export mediated regulation of microRNAs: potential target for drug intervention Curr. Drug Targets 2013 14 1094 1100 10.2174/1389450111314100002 23834155 PMC4167361 · DOI
  24. [31]Bai B. Liu H. Laiho M. Small RNA expression and deep sequencing analyses of the nucleolus reveal the presence of nucleolus-associated miRNAs FEBS Open Bio. 2014 4 441 449 10.1016/j.fob.2014.04.010 24918059 PMC4050192 · DOI
  25. [32]Azmi A.S. Li Y. Muqbil I. Aboukameel A. Senapedis W. Baloglu E. Landesman Y. Shacham S. Kauffman M.G. Philip P.A. Exportin 1 (XPO1) inhibition leads to restoration of tumor suppressor miR-145 and consequent suppression of pancreatic cancer cell proliferation and migration Oncotarget 2017 8 82144 82155 10.18632/oncotarget.19285 29137251 PMC5669877 · DOI
  26. [33]ElMaghraby M.F. Andersen P.F. Puhringer F. Hohmann U. Meixner K. Lendl T. Tirian L. Brennecke J. A Heterochromatin-Specific RNA Export Pathway Facilitates piRNA Production Cell 2019 178 964 979 10.1016/j.cell.2019.07.007 31398345 · DOI
  27. [34]Wahba A. Rath B.H. O’Neill J.W. Camphausen K. Tofilon P.J. The XPO1 inhibitor Selinexor Inhibits Translation and Enhances the Radiosensitivity of Glioblastoma Cells Growth In Vitro and In Vivo Mol. Cancer Ther. 2018 17 1717 1726 10.1158/1535-7163.MCT-17-1303 29866745 PMC6072610 · DOI
  28. [35]Von Fallois M. Depping R. Radiation Response enhanced by inhibition of XPO1 in preclinical rectal cancer models Strahlenther Onkol. 2016 192 961 962 10.1007/s00066-016-1060-2 27757501 · DOI
  29. [36]Maeda M. Moro H. Ushijima T. Mechanisms for the induction of gastric cancer by Helicobacter pylori infection: abhorrent DNA methylation pathway Gastric. Cancer 2017 20 8 15 10.1007/s10120-016-0650-0 27718135 · DOI
  30. [37]Yadav R.P. Ghatak S. Chakraborty P. Lalrohlui F. Kannan R. Kumar R. Lifestyle chemical carcinogens associated with mutations in cell cycle regulatory genes increases the susceptibility to gastric cancer risk Environ. Sci. Pollut. Res. Int. 2018 25 31691 31704 10.1007/s11356-018-3080-1 30209766 · DOI
  31. [38]Iizasa H. Nanbo A. Nishikawa J. Jinushi M. Yosiyama H. Epstein-Barr virus (EBV) associated gastric Carcinoma Viruses 2012 4 3420 3439 10.3390/v4123420 23342366 PMC3528272 · DOI
  32. [39]Ford A.C. Forman D. Hunt R.H. Yuan Y. Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomized controlled trials Bmj 2014 348 3174 10.1136/bmj.g3174 24846275 PMC4027797 · DOI
  33. [40]Cohen J.I. Epstein-barr virus vaccines Clin. Transl. Immunol. 2015 4 e32 10.1038/cti.2014.27 25671130 PMC4318489 · DOI
  34. [41]Figueiredo J. Melo S. Gamet K. Godwin T. Seixas S. Sanches J.M. Guilford P. Seruca R. E-Cadherin signal sequence disruption: a novel mechanism underlying hereditary cancer Mol Cancer. 2018 17 112 10.1186/s12943-018-0859-0 30068367 PMC6090902 · DOI
  35. [42]Cavanagh H. Rogers K.M.A. The role of BRCA1 and BRCA2 mutations in prostate, pancreatic and stomach cancers Hered. Cancer Clin. Pr. 2015 13 16 10.1186/s13053-015-0038-x PMC4521499 26236408 · DOI
  36. [43]Capelle L.G. Van Grieken N.C. Lingsma H.F. Steyerberg E.W. Klokman W.J. Bruno M.J. Vasen H.F. Kuipers E.J. Risk and epidemiological time treads of gastric cancer in Lynch syndrome carriers in the Netherlands Gastroenterology 2010 132 487 492 10.1053/j.gastro.2009.10.051 19900449 · DOI
  37. [44]Bhat S.A. Mir M.R. Majid S. Rehman M.U. Kuchy S. Sheikh B.A. Husain I. Das B. Environmental Factors in Etiology of Gastric Cancer Adv. Biochem. 2015 3 51 56 10.11648/j.ab.20150305.11 · DOI
  38. [45]Bhandare M.S. AN Kumar N. Batra S. Chaudhari V. Shrikhande S.V. Radical gastrectomy for gastric cancer at Tata Memorial Hospital Indian J. Cancer. 2017 54 605 608 10.4103/ijc.IJC_665_17 30082543 · DOI
  39. [46]Al-Batran S.E. Homann N. Pauligk C. Goetze T.O. Meiler J. Kasper S. Koop H.G. Mayer F. Haag G.M. Luley K. Preoperative chemotherapy with fluorouracil plus leucovorin, Oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomized, phase 2/3 trial Lancet 2019 393 1948 1957 10.1016/S0140-6736(18)32557-1 30982686 · DOI
  40. [48]Hing Z.A. Fung H.Y. Ranganathan P. Mitchell S. El-Gamal D. Woyach J.A. Williams K. Goettl V.M. Smith J. Yu X. Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies Leukemia 2016 30 2364 2372 10.1038/leu.2016.136 27323910 PMC5143172 · DOI
  41. [49]Subhash W. Yeo M.S. Wang L. Tan S.H. Wong F.Y. Thuya W.L. Tan W.L. Peethala P.C. Soe M.Y. Tan D.S.P. Anti-tumor efficacy of Selinexor (KPT-330) in gastric cancer is dependent on nuclear accumulation of p53 tumor suppressor Sci. Rep. 2018 8 12248 10.1038/s41598-018-30686-1 30115935 PMC6095850 · DOI
  42. [50]Li P.F. Chen S.C. Xia T. Jiang X.M. Shao Y.F. Xiao B.X. Guo J.M. Non-coding RNAs in gastric cancer World J. Gastroenterol. 2014 20 5411 5419 10.3748/wjg.v20.i18.5411 24833871 PMC4017056 · DOI
  43. [51]Zhuo W. Liu Y. Li S. Guo D. Sun Q. Jin J. Rao X. Li M. Sun M. Jiang M. Long Noncoding RNA GMAN, Up-regulated in Gastric Cancer Tissues, Is Associated with Metastasis in Patients and Promotes Translation of Ephrin A1 by Competitively Binding GMAN-AS Gastroenterol. 2019 156 676 691 10.1053/j.gastro.2018.10.054 30445010 · DOI
  44. [52]Xu Z. Yu Z. Tan Q. Wei C. Tang Q. Wang L. Hong Y. MIR-876-5p regulates gastric cancer cell proliferation, apoptosis and migration through targeting WNT5A and MITF Biosci. Rep. 2019 39 10.1042/BSR20190066 31171711 PMC6597843 · DOI
  45. [53]Archbold H.C. Jackson K.L. Arora A. Westkamp K. Tank E.M. Li X. Miguez R. Dayton R.D. Tamir S. Klein R.L. TDP43 nuclear export and neurodegeneration in models of amyotrophic lateral sclerosis and frontotemporal dementia Sci. Rep. 2018 8 4606 10.1038/s41598-018-22858-w 29545601 PMC5854632 · DOI
  46. [54]Caceres-Gorriti K.Y. Carmona E. Barres V. Rahimi K. Letourneau I.J. Tonin P.N. Provencher D. Mes-Masson A.M. RAN nucleo-cytoplasmic transport and mitotic spindle assembly partners XPO7 and TPX2 are new prognostic biomarkers in serous epithelial ovarian cancer PLoS ONE 2014 9 e91000 10.1371/journal.pone.0091000 24625450 PMC3953127 · DOI
  47. [55]Chou Y.H. Yoo Y.H. Taxol-induced growth arrest and apoptosis is associated with the upregulation of the Cdk inhibitor, p21WAF1/CIP1, in human breast cancer cells Oncol. Rep. 2012 28 2163 2169 10.3892/or.2012.2060 23023313 · DOI
  48. [56]Pluthero F.G. Kahr W.H.A. Balancing the yin and yang of SINE Blood 2017 130 1077 1078 10.1182/blood-2017-07-793398 28860324 · DOI
  49. [57]Lee J.W. Sung J.S. Park Y.S. Chung S. Kim Y.H. Isolation of Spheroid-forming single cells from gastric cancer cell lines: enrichment of cancer stem-like cells Biotechniques 2018 65 197 203 10.2144/btn-2018-0046 30284938 · DOI

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Authors
Sexton, R., Mahdi, Z., Chaudhury, R., Beydoun, R., Aboukameel, A., Khan, H. Y., Baloglu, E., Senapedis, W., Landesman, Y., Tesfaye, A., Kim, S., Philip, P. A., & Azmi, A. S.
Affiliations
  • Wayne State University (US)
  • Emory University (US)
  • Karyopharm Therapeutics (United States) (US)
Corresponding author
Azmi, Asfar S.
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2019-09-28
Volume
20
Issue
19
Pages
4826
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms20194826
PMC
PMC6801932
OpenAlex
W2975382763
Cited by
47
References
0
Citations by year
2026: 4 · 2025: 6 · 2024: 4 · 2023: 12 · 2022: 9 · 2021: 6 · 2020: 5 · 2019: 1
FWCI
1.74
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Cancer Institute (R37CA215427)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
Keywords
CRM1, gastric cancer, selective inhibitor of nuclear export, selinexor, eltanexor, leptomycin B, non-coding RNA, microRNA, apoptosis, G1/S cell cycle arrest, metastatic gastric cancer
MeSH terms
Exportin 1 Protein, Antineoplastic Agents, Cell Nucleus, Cell Survival, Humans, Stomach Neoplasms, Apoptosis, Paclitaxel, Receptors, Cytoplasmic and Nuclear, Active Transport, Cell Nucleus, Karyopherins, Cell Line, Tumor

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