Nuclear export of proteins and drug resistance in cancer.
The intracellular location of a protein is crucial to its normal functioning in a cell. Cancer cells utilize the normal processes of nuclear-cytoplasmic transport through the nuclear pore complex of a cell to effectively evade anti-neoplastic mechanisms. CRM1-mediated export is increased in various cancers. Proteins that are exported in cancer include tumor-suppressive proteins such as retinoblastoma, APC, p53, BRAC1, FOXO proteins, INI1/hSNF5, galectin-3, Bok, nucleophosmin, RASSF2, Merlin, p21(CIP), p27(KIP1), N-WASP/FAK, estradiol receptor and Tob, drug targets topoisomerase I and IIα and BCR-ABL, and the molecular chaperone protein Hsp90. Here, we review in detail the current processes and known structures involved in the export of a protein through the nuclear pore complex. We also discuss the export receptor molecule CRM1 and its binding to the leucine-rich nuclear export signal of the cargo protein and the formation of a nuclear export trimer with RanGTP. The therapeutic potential of various CRM1 inhibitors will be addressed, including leptomycin B, ratjadone, KOS-2464, and specific small molecule inhibitors of CRM1, N-azolylacrylate analogs, FOXO export inhibitors, valtrate, acetoxychavicol acetate, CBS9106, and SINE inhibitors. We will also discuss examples of how drug resistance may be reversed by targeting the exported proteins topoisomerase IIα, BCR-ABL, and galectin-3. As effective and less toxic CRM1 export inhibitors become available, they may be used as both single agents and in combination with current chemotherapeutic drugs. We believe that the future development of low-toxicity, small-molecule CRM1 inhibitors may provide a new approach to treating cancer.
Blood and Marrow Transplant Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Joel G
JG
Turner
Jana
J
Dawson
Daniel M
DM
Sullivan
D021581:Active Transport, Cell Nucleus / Q000187:drug effects* / Q000502:physiology*; D000631:Aminopyridines / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D037502:Galectin 3 / Q000378:metabolism; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097606:Exportin 1 Protein
D000631:Aminopyridines; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D005231:Fatty Acids, Unsaturated; D037502:Galectin 3; D028884:Karyopherins; D011506:Proteins; D011753:Pyrones; D011760:Pyrrolidinones; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C568326:CBS 9106; C429103:ratjadone; C038753:leptomycin B