Document Detail


Circulating serpin tumor markers SCCA1 and SCCA2 are not actively secreted but reside in the cytosol of squamous carcinoma cells.
MedLine Citation:
PMID:  10956412     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
An elevation in the circulating level of the squamous-cell carcinoma antigen (SCCA) can be a poor prognostic indicator in certain types of squamous-cell cancers. Total SCCA in the circulation comprises 2 nearly identical, approximately 45 kDa proteins, SCCA1 and SCCA2. Both proteins are members of the high-molecular weight serine proteinase inhibitor (serpin) family with SCCA1 paradoxically inhibiting lysosomal cysteine proteinases and SCCA2 inhibiting chymotrypsin-like serine proteinases. Although SCCA1 and SCCA2 are detected in the cytoplasm of normal squamous epithelial cells, neither serpin is detected normally in the serum. Thus, their presence in the circulation at relatively high concentrations suggests that malignant epithelial cells are re-directing serpin activity to the fluid phase via an active secretory process. Because serpins typically inhibit their targets by binding at 1:1 stoichiometry, a change in the distribution pattern of SCCA1 and SCCA2 (i.e., intracellular to extracellular) could indicate the need of tumor cells to neutralize harmful extracellular proteinases. The purpose of our study was to determine experimentally the fate of SCCA1 and SCCA2 in squamous carcinoma cells. Using subcellular fractionation, SCCA-green fluorescent fusion protein expression and confocal microscopy, SCCA1 and SCCA2 were found exclusively in the cytosol and were not associated with nuclei, mitochondria, lysosomes, microtubules, actin or the Golgi. In contrast to previous reports, metabolic labeling and pulse-chase experiments showed that neither non-stimulated nor TNFalpha/PMA-stimulated squamous carcinoma cells appreciably secreted these ov-serpins into the medium. Collectively, these data suggest that the major site of SCCA1 and SCCA2 inhibitory activity remains within the cytosol and that their presence in the sera of patients with advanced squamous-cell carcinomas may be due to their passive release into the circulation.
Authors:
Y Uemura; S C Pak; C Luke; S Cataltepe; C Tsu; C Schick; Y Kamachi; S L Pomeroy; D H Perlmutter; G A Silverman
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  89     ISSN:  0020-7136     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2000 Jul 
Date Detail:
Created Date:  2000-08-31     Completed Date:  2000-08-31     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  368-77     Citation Subset:  IM    
Copyright Information:
Copyright 2000 Wiley-Liss, Inc.
Affiliation:
Division of Newborn Medicine, Department of Pediatrics, Harvard Medical School, Children's Hospital, Boston, MA 02115-5737, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Antigens, Neoplasm / blood,  metabolism*
COS Cells
Cytosol / metabolism
Endopeptidases / metabolism
Female
Head and Neck Neoplasms / blood,  metabolism,  secretion
Humans
Molecular Sequence Data
Protease Inhibitors / blood,  metabolism
Sequence Homology, Amino Acid
Serpins / blood,  metabolism,  secretion*
Subcellular Fractions / metabolism
Tetradecanoylphorbol Acetate / pharmacology
Tumor Cells, Cultured
Tumor Markers, Biological / blood,  metabolism,  secretion*
Tumor Necrosis Factor-alpha / pharmacology
Uterine Cervical Neoplasms / blood,  metabolism,  secretion
Grant Support
ID/Acronym/Agency:
CA69331/CA/NCI NIH HHS; CA73031/CA/NCI NIH HHS; HD28475/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, Neoplasm; 0/Protease Inhibitors; 0/Serpins; 0/Tumor Markers, Biological; 0/Tumor Necrosis Factor-alpha; 0/squamous cell carcinoma-related antigen; 16561-29-8/Tetradecanoylphorbol Acetate; EC 3.4.-/Endopeptidases

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