Nuclear Export as a Novel Therapeutic Target: The CRM1 Connection.
The integrity of eukaryotic cellular function depends on molecular and biochemical compartmentalization. The transport of macromolecules between compartments requires specific and energydriven mechanisms. It occurs through a class of transport proteins known as karyopherins, which are divided in three different groups (exportins, importins, and transportins). The ubiquitous exportin Chromosome Region Maintenance 1 (CRM1) is involved in the transport of many proteins and RNA molecules from nucleus to cytoplasm. We have reviewed the available evidence supporting the relevance of CRM1 in the biology of several human neoplasms, its potential role in drug resistance, and its promise as a therapeutic target. Here we discuss different cancer related proteins (tumor suppressor genes, oncogenes, and enzymatic therapeutic targets), their function, and their association with CRM1, as well as agents that specifically inhibit CRM1, their mechanism of action, and their clinical relevance in certain human neoplasms. The directionality of nuclear transport and the specific molecular cargo in question are of paramount importance when examining the effects that CRM1 inhibition may have on cellular pathophysiology. The available data point out the potential role of CRM1-dependent nuclear export of regulatory proteins in the biology of certain human malignancies. Further studies should expand and clarify the importance of this mechanism in the pathobiology of human neoplasia.
Chuanwen
C
Lu
Jose A
JA
Figueroa
Zhongwei
Z
Liu
Venu
V
Konala
Amardeep
A
Aulakh
Rashmi
R
Verma
Everardo
E
Cobos
Maurizio
M
Chiriva-Internati
Center for Blood Disorders and Cancer Therapeutics, Grace Health System, 2412 50th street, Lubbock, TX 79412, USA. jfigueroa@kiromic.com.
Weimin
W
Gao
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097606:Exportin 1 Protein
D000970:Antineoplastic Agents; D028884:Karyopherins; D009363:Neoplasm Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein