Article ; Online: Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB.
Molecular and cellular biology
2016 Volume 36, Issue 12, Page(s) 1776–1792
Abstract: We and others have shown that the cystatin E/M gene is inactivated in primary human tumors, pointing to its role as a tumor suppressor gene. However, the molecular mechanism of tumor suppression is not yet understood. Using plasmid-directed cystatin E/M ... ...
| Abstract | We and others have shown that the cystatin E/M gene is inactivated in primary human tumors, pointing to its role as a tumor suppressor gene. However, the molecular mechanism of tumor suppression is not yet understood. Using plasmid-directed cystatin E/M gene overexpression, a lentivirus-mediated tetracycline-inducible vector system, and human papillomavirus 16 (HPV 16) E6 and E7 gene-immortalized normal human epidermal keratinocytes, we demonstrated intracellular and non-cell-autonomous apoptotic growth inhibition of tumor cell lines and that growth inhibition is associated with cytoplasmic retention of NF-κB. We further demonstrated decreased phosphorylation of IκB kinase (IKKβ) and IκBα in the presence of tumor necrosis factor alpha (TNF-α), confirming the role of cystatin E/M in the regulation of the NF-κB signaling pathway. Growth suppression of nude mouse xenograft tumors carrying a tetracycline-inducible vector system was observed with the addition of doxycycline in drinking water, confirming that the cystatin E/M gene is a tumor suppressor gene. Finally, immunohistochemical analyses of cervical carcinoma in situ and primary tumors have shown a statistically significant inverse relationship between the expression of cystatin E/M and cathepsin L and a direct relationship between the loss of cystatin E/M expression and nuclear expression of NF-κB. We therefore propose that the cystatin E/M suppressor gene plays an important role in the regulation of NF-κB. |
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| MeSH term(s) | Animals ; Cathepsin L/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cystatin M/genetics ; Cystatin M/metabolism ; Cytoplasm/metabolism ; Doxycycline/administration & dosage ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Vectors/pharmacology ; HeLa Cells ; Humans ; I-kappa B Proteins/metabolism ; Lentivirus/genetics ; Mice ; Mice, Nude ; NF-kappa B/metabolism ; Neoplasm Transplantation ; Phosphorylation ; Signal Transduction ; Tumor Necrosis Factor-alpha/metabolism ; Uterine Cervical Neoplasms/genetics ; Uterine Cervical Neoplasms/metabolism ; Uterine Cervical Neoplasms/pathology |
| Chemical Substances | CST6 protein, human ; Cystatin M ; I-kappa B Proteins ; NF-kappa B ; TNF protein, human ; Tumor Necrosis Factor-alpha ; CTSL protein, human (EC 3.4.22.15) ; Cathepsin L (EC 3.4.22.15) ; Doxycycline (N12000U13O) |
| Language | English |
| Publishing date | 2016-05-31 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 779397-2 |
| ISSN | 1098-5549 ; 0270-7306 |
| ISSN (online) | 1098-5549 |
| ISSN | 0270-7306 |
| DOI | 10.1128/MCB.00878-15 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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