Targeting of nucleo‑cytoplasmic transport factor exportin 1 in malignancy

Abstract

Nuclear pore complexes (NPCs) regulate the entry and exit of molecules from the cell nucleus. Small molecules pass through NPCs by diffusion while large molecules enter and exit the nucleus by karyopherins, which serve as transport factors. Exportin-1 (XPo1) is a protein that is an important member of the karyopherin family and carries macromolecules from the nucleus to the cytoplasm. XPo1 is responsible for nuclear-cytoplasmic transport of protein, ribosomal rNa and certain required mrNas for ribosomal biogenesis. Furthermore, XPo1-mediated nuclear export is associated with various types of disease, such as cancer, inflammation and viral infection. the key role of XPo1 in carcinogenesis and its potential as a therapeutic target has been demonstrated by previous studies. Clinical use of novel developed generation-specific XPO1 inhibitors and their combination with other agents to block XPo1-mediated nuclear export are a promising new treatment strategy. the aim of the present study was to explain the working mechanism of XPo1 and inhibitors that block XPo1-mediated nuclear export. Contents 1. Nucleo-cytoplasmic transport 2. Structure of XPo1 3. Physiological function of XPo1 in cells 4. XPo1 export of protein 5. Single nucleotide polymorphisms (SNPs) of XPo1 6. XPo1 in cancer 7. Inhibitors of XPo1 8. Conclusion and future directions

CRM1 expression: association with high prognostic value in laryngeal cancer

“…It can be used in the development of new treatment strategies for laryngeal cancer patients with increased CRM1 expression level. Dysregulation of CRM1 has been shown to be associated with increased expression in many types of cancer, particularly solid tumors [ 19 ]. As far as we know, this is the first study to report elevated CRM1 expression as an independent prognostic marker for poor clinical course and overall survival in laryngeal cancer patients diagnosed with squamous cell carcinoma.…”

“…It has been reported that Nuclear transcription factor Y (NFY)/CREB-binding protein (CBP), Sp1 transcription factor (SP1), and tumor protein p53 (P53) transcription factors interact with the promoter of the CRM1 gene and together play an important role in the transformation of cancer cells [ 46 ]. In previous studies, it has been reported that the specific inhibition of CRM1 increases the nuclear uptake and expression of major tumor suppressor proteins such as RB, P53, P21, P33, FOXO, P27, and decreases the expression of oncogenic proteins such as MYC, MET, and EGFR [ 9 , 10 , 19 ]. CRM1 is the solo nuclear transporter of many proteins with prognostic value in laryngeal cancer, such as P53, P16, P63, Rb, PTEN, Nuclear factor kappa B (NFκB), EGFR, Cyclin D1, Survivin, and BCL-2 [ 9 , 19 , 46 , 47 ].…”

“…In previous studies, it has been reported that the specific inhibition of CRM1 increases the nuclear uptake and expression of major tumor suppressor proteins such as RB, P53, P21, P33, FOXO, P27, and decreases the expression of oncogenic proteins such as MYC, MET, and EGFR [ 9 , 10 , 19 ]. CRM1 is the solo nuclear transporter of many proteins with prognostic value in laryngeal cancer, such as P53, P16, P63, Rb, PTEN, Nuclear factor kappa B (NFκB), EGFR, Cyclin D1, Survivin, and BCL-2 [ 9 , 19 , 46 , 47 ]. In addition, in vitro and in vivo studies and bioinformatic analyses have shown that CRM1 promotes cancer in the cell by suppressing the immune response in the microenvironment through various biological pathways [ 10 , 48 ].…”

“…By inhibiting CRM1 function, enabling various tumor suppressor proteins to accumulate in the nucleus, and activating apoptotic pathways may enable the development of new molecule-targeted therapy strategies [ 49 ]. Recently, several synthetic CRM1-inhibitors have been developed, such as the new generation PKF050-638, CBS9106, and Selective Nuclear Export inhibitors (SINEs) including KPT-185, KPT-276, Verdinexor (KPT-335), Selinexor (KPT-330), Eltanexor (KPT-8602), and Felezonexor (SL-801) which are less toxic, semireversible inhibitors instead of the first inhibitor LMB [ 19 , 50 ]. A number of SINE compounds, showing efficacy in solid tumors [ 44 , 50 ] and hematopoietic malignancies [ 41 , 52 , 53 ], have been extensively tested in preclinical settings.…”

“…CRM1 was reported to be overexpressed in many human cancers and its overexpression is associated with aggressive behavior and poor survival [ 13 – 18 ]. The biological role of CRM1 in laryngeal cancer have not yet been evaluated [ 8 – 10 , 19 ].…”