Inhibiting Cancer Cell Hallmark Features Through Nuclear Export Inhibition

Overview

Journal Signal Transduct Target Ther

Specialties Cell Biology
Pharmacology

Date 2017 Dec 22

PMID 29263896

Citations 57

Authors

Qingxiang Sun

Xueqin Chen

Qiao Zhou

Ezra Burstein

Shengyong Yang

Da Jia

Affiliations

Soon will be listed here.

Abstract

Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

Citing Articles

Strategies for the Viral Exploitation of Nuclear Pore Transport Pathways.

Zhang X, Lim K, Qiu Y, Hazawa M, Wong R Viruses. 2025; 17(2).

PMID: 40006906 PMC: 11860923. DOI: 10.3390/v17020151.

Discovery, Validation and Mechanistic Study of XPO1 Inhibition in the Treatment of Triple-Negative Breast Cancer.

Paulson A, Gruener R, Lee A, Huang R Cancers (Basel). 2024; 16(23).

PMID: 39682167 PMC: 11640544. DOI: 10.3390/cancers16233980.

The Potential of Nuclear Pore Complexes in Cancer Therapy.

Zaitsava H, Gachowska M, Bartoszewska E, Kmiecik A, Kulbacka J Molecules. 2024; 29(20).

PMID: 39459201 PMC: 11510365. DOI: 10.3390/molecules29204832.

Michael Acceptors as Anti-Cancer Compounds: Coincidence or Causality?.

Andres C, Perez de la Lastra J, Munguira E, Juan C, Perez-Lebena E Int J Mol Sci. 2024; 25(11).

PMID: 38892287 PMC: 11172677. DOI: 10.3390/ijms25116099.

The nuclear export protein exportin-1 in solid malignant tumours: From biology to clinical trials.

Lai C, Xu L, Dai S Clin Transl Med. 2024; 14(5):e1684.

PMID: 38783482 PMC: 11116501. DOI: 10.1002/ctm2.1684.

References

Shen A, Wang Y, Zhao Y, Zou L, Sun L, Cheng C . Expression of CRM1 in human gliomas and its significance in p27 expression and clinical prognosis. Neurosurgery. 2009; 65(1):153-9. DOI: 10.1227/01.NEU.0000348550.47441.4B. View

Breit M, Kisseberth W, Bear M, Landesman Y, Kashyap T, McCauley D . Biologic activity of the novel orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 against canine melanoma cell lines. BMC Vet Res. 2014; 10:160. PMC: 4105800. DOI: 10.1186/1746-6148-10-160. View

Weis K . Importins and exportins: how to get in and out of the nucleus. Trends Biochem Sci. 1998; 23(5):185-9. DOI: 10.1016/s0968-0004(98)01204-3. View

Moriggi G, Nieto B, Dosil M . Rrp12 and the Exportin Crm1 participate in late assembly events in the nucleolus during 40S ribosomal subunit biogenesis. PLoS Genet. 2014; 10(12):e1004836. PMC: 4256259. DOI: 10.1371/journal.pgen.1004836. View

Wach J, Guttinger S, Kutay U, Gademann K . The cytotoxic styryl lactone goniothalamin is an inhibitor of nucleocytoplasmic transport. Bioorg Med Chem Lett. 2010; 20(9):2843-6. DOI: 10.1016/j.bmcl.2010.03.049. View

van der Watt P, Zemanay W, Govender D, Hendricks D, Parker M, Leaner V . Elevated expression of the nuclear export protein, Crm1 (exportin 1), associates with human oesophageal squamous cell carcinoma. Oncol Rep. 2014; 32(2):730-8. DOI: 10.3892/or.2014.3231. View

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View

Pennisi R, Ascenzi P, Di Masi A . Hsp90: A New Player in DNA Repair?. Biomolecules. 2015; 5(4):2589-618. PMC: 4693249. DOI: 10.3390/biom5042589. View

Harley C . Telomerase and cancer therapeutics. Nat Rev Cancer. 2008; 8(3):167-79. DOI: 10.1038/nrc2275. View

10.

Van Neck T, Pannecouque C, Vanstreels E, Stevens M, Dehaen W, Daelemans D . Inhibition of the CRM1-mediated nucleocytoplasmic transport by N-azolylacrylates: structure-activity relationship and mechanism of action. Bioorg Med Chem. 2008; 16(21):9487-97. DOI: 10.1016/j.bmc.2008.09.051. View

11.

Bischoff F, Klebe C, Kretschmer J, Wittinghofer A, Ponstingl H . RanGAP1 induces GTPase activity of nuclear Ras-related Ran. Proc Natl Acad Sci U S A. 1994; 91(7):2587-91. PMC: 43414. DOI: 10.1073/pnas.91.7.2587. View

12.

Sun Q, Carrasco Y, Hu Y, Guo X, Mirzaei H, MacMillan J . Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1. Proc Natl Acad Sci U S A. 2013; 110(4):1303-8. PMC: 3557022. DOI: 10.1073/pnas.1217203110. View

13.

Inoue H, Kauffman M, Shacham S, Landesman Y, Yang J, Evans C . CRM1 blockade by selective inhibitors of nuclear export attenuates kidney cancer growth. J Urol. 2012; 189(6):2317-26. PMC: 4593314. DOI: 10.1016/j.juro.2012.10.018. View

14.

Gao J, Azmi A, Aboukameel A, Kauffman M, Shacham S, Abou-Samra A . Nuclear retention of Fbw7 by specific inhibitors of nuclear export leads to Notch1 degradation in pancreatic cancer. Oncotarget. 2014; 5(11):3444-54. PMC: 4116494. DOI: 10.18632/oncotarget.1813. View

15.

Lapalombella R, Sun Q, Williams K, Tangeman L, Jha S, Zhong Y . Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood. 2012; 120(23):4621-34. PMC: 3512237. DOI: 10.1182/blood-2012-05-429506. View

16.

Kalgutkar A, Dalvie D . Drug discovery for a new generation of covalent drugs. Expert Opin Drug Discov. 2012; 7(7):561-81. DOI: 10.1517/17460441.2012.688744. View

17.

London C, Feo Bernabe L, Barnard S, Kisseberth W, Borgatti A, Henson M . Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study. PLoS One. 2014; 9(2):e87585. PMC: 3913620. DOI: 10.1371/journal.pone.0087585. View

18.

Crochiere M, Baloglu E, Klebanov B, Donovan S, Del Alamo D, Lee M . A method for quantification of exportin-1 (XPO1) occupancy by Selective Inhibitor of Nuclear Export (SINE) compounds. Oncotarget. 2015; 7(2):1863-77. PMC: 4811503. DOI: 10.18632/oncotarget.6495. View

19.

Wang D, Wang Y, Lu P, E Q, Shi G . [Expression of nuclear export factor CRM1 and p27 in glioma]. Zhonghua Bing Li Xue Za Zhi. 2008; 37(7):454-7. View

20.

Hamamoto T, Uozumi T, Beppu T . Leptomycins A and B, new antifungal antibiotics. III. Mode of action of leptomycin B on Schizosaccharomyces pombe. J Antibiot (Tokyo). 1985; 38(11):1573-80. DOI: 10.7164/antibiotics.38.1573. View