dynorphins and Lung-Neoplasms

Functional evidence suggests that opioid peptides such as dynorphin are involved in the regulation of airway macrophage functions and of human cancer growth. However, anatomical evidence for components of a putative dynorphin network within lung cancer patients is scarce. Tissue from lung cancer patients was examined immunohistochemically for all components of a local dynorphin (DYN) network. Double immunofluorescence microscopy analysis revealed colocalization of the opioid precursor PDYN with its end-product DYN, and key processing enzymes prohormone convertases 1 and 2 and carboxypeptidase E, as well as the kappa-opioid receptor (KOR) within alveolar macrophages and cancerous cells in varying degrees among patients. Moreover, chromograninA-immunoreactive pulmonary neuroendocrine cells expressing DYN were close to substance P- and KOR-immunoreactive sensory nerves. Our findings give a first hint of a neuroanatomical basis for a peripheral DYN network, conceivably regulating pulmonary, immune and cell-proliferative functions within the human lung, most likely in a paracrine/autocrine fashion.

Topics: Aged; Biomarkers, Tumor; Bronchi; Carboxypeptidase H; Carcinoma; Dynorphins; Enkephalins; Female; Fluorescent Antibody Technique, Indirect; Humans; Immunoenzyme Techniques; Lung Neoplasms; Macrophages, Alveolar; Male; Microscopy, Fluorescence; Middle Aged; Neurotransmitter Agents; Proprotein Convertase 1; Proprotein Convertase 2; Protein Precursors; Receptors, Opioid, kappa; Respiratory Mucosa

A novel soluble non-opioid dynorphin A-binding factor (DABF) was identified and characterized in neuronal cell lines, rat spinal cord, and brain. DABF binds dynorphin A(1-17), dynorphin A(2-17), and the 32 amino acid prodynorphin fragment big dynorphin consisting of dynorphin A and B, but not other opioid and non-opioid peptides, opiates, and benzomorphans. The IC50 for dynorphin A(1-17), dynorphin A(2-17), and big dynorphin is in the 5-10 nM range. Using dynorphin A and big dynorphin fragments a binding epitope was mapped to dynorphin A(6-13). DABF has a molecular mass of about 70 kDa. SH-groups are apparently involved in the binding of dynorphin A since p-hydroxy-mercuribenzoic acid inhibited this process. Upon interaction with DABF dynorphin A was converted into Leu-enkephalin, which remained bound to the protein. These data suggest that DABF functions as an oligopeptidase that forms stable and specific complexes with dynorphin A. The presence of DABF in brain structures and other tissues with low level of prodynorphin expression suggests that DABF as an oligopeptidase may degrade other peptides. Dynorphin A at the sites of its release in the CNS may attenuate this degradation as a competitor when it specifically binds to the enzyme.

Topics: Animals; Brain; Carcinoma, Small Cell; Carrier Proteins; Cell Line; Cell Line, Tumor; Choriocarcinoma; DDT; Dynorphins; Humans; Hydroxymercuribenzoates; Kinetics; Lung Neoplasms; Mice; Mice, Inbred Strains; Nerve Tissue Proteins; Neuroblastoma; Neurons; Protease Inhibitors