Targeting Nucleocytoplasmic Transport in Cancer Therapy

Overview

Journal Oncotarget

Specialty Oncology

Date 2014 Jan 17

PMID 24429466

Citations 53

Authors

Richard Hill

Bastien Cautain

Nuria de Pedro

Wolfgang Link

Affiliations

Soon will be listed here.

Abstract

The intracellular location and regulation of proteins within each cell is critically important and is typically deregulated in disease especially cancer. The clinical hypothesis for inhibiting the nucleo-cytoplasmic transport is based on the dependence of certain key proteins within malignant cells. This includes a host of well-characterized tumor suppressor and oncoproteins that require specific localization for their function. This aberrant localization of tumour suppressors and oncoproteins results in their their respective inactivation or over-activation. This incorrect localization occurs actively via the nuclear pore complex that spans the nuclear envelope and is mediated by transport receptors. Accordingly, given the significant need for novel, specific disease treatments, the nuclear envelope and the nuclear transport machinery have emerged as a rational therapeutic target in oncology to restore physiological nucleus/cytoplasmic homeostasis. Recent evidence suggests that this approach might be of substantial therapeutic use. This review summarizes the mechanisms of nucleo-cytoplasmic transport, its role in cancer biology and the therapeutic potential of targeting this critical cellular process.

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References

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

Kau T, Way J, Silver P . Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer. 2004; 4(2):106-17. DOI: 10.1038/nrc1274. View

Ambrus G, Whitby L, Singer E, Trott O, Choi E, Olson A . Small molecule peptidomimetic inhibitors of importin α/β mediated nuclear transport. Bioorg Med Chem. 2010; 18(21):7611-20. PMC: 2966498. DOI: 10.1016/j.bmc.2010.08.038. View

Schuchner S, Tembe V, Rodriguez J, Henderson B . Nuclear targeting and cell cycle regulatory function of human BARD1. J Biol Chem. 2005; 280(10):8855-61. DOI: 10.1074/jbc.M413741200. View

Yang H, Zhao R, Yang H, Lee M . Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity. Oncogene. 2005; 24(11):1924-35. DOI: 10.1038/sj.onc.1208352. View

Garrett J, Chakrabarty A, Arteaga C . Will PI3K pathway inhibitors be effective as single agents in patients with cancer?. Oncotarget. 2012; 2(12):1314-21. PMC: 3282088. DOI: 10.18632/oncotarget.409. View

Falini B, Nicoletti I, Martelli M, Mecucci C . Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood. 2006; 109(3):874-85. DOI: 10.1182/blood-2006-07-012252. View

Davis J, Kakar M, Lim C . Controlling protein compartmentalization to overcome disease. Pharm Res. 2006; 24(1):17-27. DOI: 10.1007/s11095-006-9133-z. View

Stengelshoj Olsen L, Vig Hjarnaa P, Latini S, Holm P, Larsson R, Bramm E . Anticancer agent CHS 828 suppresses nuclear factor-kappa B activity in cancer cells through downregulation of IKK activity. Int J Cancer. 2004; 111(2):198-205. DOI: 10.1002/ijc.20255. View

10.

Corvi R, Savelyeva L, Breit S, Wenzel A, Handgretinger R, Barak J . Non-syntenic amplification of MDM2 and MYCN in human neuroblastoma. Oncogene. 1995; 10(6):1081-6. View

11.

Hilmi C, Larribere L, Deckert M, Rocchi S, Giuliano S, Bille K . Involvement of FKHRL1 in melanoma cell survival and death. Pigment Cell Melanoma Res. 2008; 21(2):139-46. DOI: 10.1111/j.1755-148X.2008.00440.x. View

12.

Gavathiotis E, Reyna D, Bellairs J, Leshchiner E, Walensky L . Direct and selective small-molecule activation of proapoptotic BAX. Nat Chem Biol. 2012; 8(7):639-45. PMC: 3617124. DOI: 10.1038/nchembio.995. View

13.

Zhang Y, Carr T, Dimtchev A, Zaer N, Dritschilo A, Jung M . Attenuated DNA damage repair by trichostatin A through BRCA1 suppression. Radiat Res. 2007; 168(1):115-24. DOI: 10.1667/RR0811.1. View

14.

Ronca F, Yee K, Yu V . Retinoic acid confers resistance to p53-dependent apoptosis in SH-SY5Y neuroblastoma cells by modulating nuclear import of p53. J Biol Chem. 1999; 274(25):18128-34. DOI: 10.1074/jbc.274.25.18128. View

15.

Hu M, Lee D, Xia W, Golfman L, Ou-Yang F, Yang J . IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004; 117(2):225-37. DOI: 10.1016/s0092-8674(04)00302-2. View

16.

Verdine G, Walensky L . The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin Cancer Res. 2007; 13(24):7264-70. DOI: 10.1158/1078-0432.CCR-07-2184. View

17.

Wells J, McClendon C . Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature. 2007; 450(7172):1001-9. DOI: 10.1038/nature06526. View

18.

Fabbro M, Rodriguez J, Baer R, Henderson B . BARD1 induces BRCA1 intranuclear foci formation by increasing RING-dependent BRCA1 nuclear import and inhibiting BRCA1 nuclear export. J Biol Chem. 2002; 277(24):21315-24. DOI: 10.1074/jbc.M200769200. View

19.

Brown C, Lain S, Verma C, Fersht A, Lane D . Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009; 9(12):862-73. DOI: 10.1038/nrc2763. View

20.

Moreno-Bueno G, Rodriguez-Perales S, Sanchez-Estevez C, Hardisson D, Sarrio D, Prat J . Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene. 2003; 22(38):6115-8. DOI: 10.1038/sj.onc.1206868. View