Researchers at The Pennsylvania State University College of Medicine, Hershey, Pennsylvania have discovered that the Opioid Growth Factor (OGF, [Met5]-enkephalin) and its receptor, OGFr, a clinically important system with potent antitumor properties, has controlled entry from the cytoplasm to the nucleus. The nucleocytoplasmic passage of OGF-OGFr is critical to cell proliferation and suggests that there are hierarchical levels of nuclear import. This discovery, reported in the September 2010 issue of Experimental Biology and Medicine, provides new insights into understanding the pathobiology of diseases related to this native biological system, and contributes to the development of new agents that will enhance treatment effectiveness.
Previous immunohistochemical and immunoelectron microscope studies have detected OGF and OGFr in both the cytoplasm and the nucleus. The OGF-OGFr axis is known to regulate cell proliferation by modulating cyclin dependent kinase inhibitors, resulting in a retardation of cells at the G1-S interface of the cell cycle. Experiments utilizing a human cancer cell line, a squamous cell carcinoma of the head and neck, and a probe of OGFr fused to green fluorescent protein (eGFP), revealed the presence of a transport factor, karyopherin β, which plays a key role in nucleocytoplasmic transport. Moreover, directionality of transport for karyopherin β is dependent on the small guanosine triphophatase (GTPase) Ran. Knockdown of karyopherin β or Ran with siRNAs, but not the adaptor molecule karyopherin α, prevented transport of OGFr-eGFP and resulted in a marked increase in DNA synthesis. These results document that the pathway for regulating the cell cycle by the OGF-OGFr axis involves the timely and faithful translocation of this peptide-receptor complex across the nuclear envelope. This nucleocytoplasmic trafficking is critical for cell proliferation.