Abstract
Recent studies have demonstrated the interference of nucleocytoplasmic trafficking with the establishment and maintenance of various cancers. Nucleocytoplasmic transport is highly regulated and coordinated, involving different nuclear transport factors or receptors, importins and exportins, that mediate cargo transport from the cytoplasm into the nucleus or the other way round, respectively. The exportin CRM1 (Chromosome region maintenance 1) exports a plethora of different protein cargoes and ribonucleoprotein complexes. Structural and biochemical analyses have enabled the deduction of individual steps of the CRM1 transport cycle. In addition, CRM1 turned out to be a valid target for anticancer drugs as it exports numerous proto-oncoproteins and tumor suppressors. Clearly, detailed understanding of the flexibility, regulatory features and cooperative binding properties of CRM1 for Ran and cargo is a prerequisite for the design of highly effective drugs. The first compound found to inhibit CRM1-dependent nuclear export was the natural drug Leptomycin B (LMB), which blocks export by competitively interacting with a highly conserved cleft on CRM1 required for nuclear export signal recognition. Clinical studies revealed serious side effects of LMB, leading to a search for alternative natural and synthetic drugs and hence a multitude of novel therapeutics. The present review examines recent progress in understanding the binding mode of natural and synthetic compounds and their inhibitory effects.
Highlights
In the early days of cancer treatment, shotgun approaches using drugs interfering with DNA replication in a more general way were used, with the consequence of massive unwanted side effects.About 30 years ago, identification of the individual proteins involved in specific cancers and an understanding of their biochemistry incited hype about having found the cure for cancer
A multitude of proteins interfering with cell regulation have been described, but the specific amount of proteins required/involved to trigger cell cancerogenesis and the specific functions including the complex interplay of these proteins is still poorly understood
The tumor suppressor protein/transcription factor p53, named according to its apparent molecular weight, is localized in the nucleus in normal cells. It is often inactivated in cancer cells due to mutations leading to a “loss of function” or p53 is delocalized into the cytoplasm due to nuclear export signal (NES) unmasking and active export [9,10] reviewed in [11,12]
Summary
In the early days of cancer treatment, shotgun approaches using drugs interfering with DNA replication in a more general way were used, with the consequence of massive unwanted side effects. About 30 years ago, identification of the individual proteins involved in specific cancers and an understanding of their biochemistry incited hype about having found the cure for cancer. A multitude of proteins interfering with cell regulation have been described, but the specific amount of proteins required/involved to trigger cell cancerogenesis and the specific functions including the complex interplay of these proteins is still poorly understood. Cure for cancer or the need for a more personalized and cancer-specific treatment targeting the individual deregulating mechanisms in each patient. Recent developments in cancer therapy reveal that the effects of specific drugs may be increased by interfering with additional macromolecular machineries in the cell [1]. This review focuses on CRM1-dependent export deregulation and effects of drugs on CRM1 function. For further reading as introduction to the complexity of cancer development, regulation and treatment, we refer to excellent reviews and perspective articles [1,2,3,4,5]
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