ABSTRACT
Activity of the proteasome, polyfunctional enzymatic complex, is known to undergo changes during cancer development. This phenomenon is, probably, caused by the changes in subunit composition of proteasomes. In present work, we studied chymotrypsin-like activity of proteasomes, subunit composition and their association in breast cancer, head and neck squamous cell carcinoma, endometrial cancer, renal cancer, bladder cancer, stomach cancer and colorectal cancer. The increase of proteasome activity was revealed in most cancer tissues compared with adjacent tissues except for the renal cell carcinoma. Changes in proteasome activity in cancer tissues compared with correspondent normal tissues were accompanied by modification of its subunit composition. High proteasome activity was observed in combination with an increased expression of immune subunits and/or proteasome activator PA28, associated with activity of 20S proteasome. In breast cancer, head and neck squamous cell carcinoma, bladder cancer, stomach cancer and colorectal cancer we additionally found higher expression of Rpt6 subunit of 26S proteasome. Correlations between chymotrypsin like proteasome activity and subunit expressions were found in human cancer tissues. In summary, we suggest that proteasome ac- tivation and changes in its subunit composition plays an important role in cancer pathogenesis.
Subject(s)
Chymases/metabolism , Neoplasms/enzymology , Proteasome Endopeptidase Complex/metabolism , ATPases Associated with Diverse Cellular Activities , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Cell Line, Tumor , Humans , LIM Domain Proteins/genetics , LIM Domain Proteins/metabolism , Muscle Proteins/genetics , Muscle Proteins/metabolism , Proteasome Endopeptidase Complex/genetics , Protein Subunits/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
We have examined for the first time the relationship between the expression of PAPP-A metalloproteinase and insulin-like growth factors (IGF-I, IGF-II, VEGF) and transcription factors (NF-kappaB, HIF-1) playing an important role in pathogenesis of cancer. We also demonstrated a positive association between the level of PAPP-A metalloproteinase and the level of growth (VEGF and IGF-I) and transcription factors (NF-kappaB p50, NF-kappaB p65, HIF-1alpha). The current findings suggest an important role of PAPP-A in regulation of bioavailability of IGF-I, VEGF, activated forms of NF-kappaB, and alpha-subunits of HIF-1 in endometrial tumors.
Subject(s)
Endometrial Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Pregnancy-Associated Plasma Protein-A/metabolism , Endometrial Neoplasms/pathology , Female , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor II/genetics , Insulin-Like Growth Factor II/metabolism , Middle Aged , NF-kappa B/genetics , NF-kappa B/metabolism , Neoplasm Staging , Pregnancy-Associated Plasma Protein-A/genetics , Transcription Factors/biosynthesis , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolismABSTRACT
The development of endometrial cancer is related to the status of the intracellular proteasome system. Total proteasome activity and pools 26S and 20S activities are higher in tumor tissue than in intact endometrium, and their composition is different. The expression of α1α2α3α5α6α7 is lower in endometrial cancer tissue in comparison with intact endometrium and the content of immune subunits LMP7, LMP2, and PA28ß is increased. Total proteasome activity depends on the disease stage.
Subject(s)
Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Endometrium/metabolism , Proteasome Endopeptidase Complex/metabolism , Protein Subunits/metabolism , Electrophoresis , Female , Humans , Middle Aged , Statistics, NonparametricABSTRACT
Insulin-like growth factors and the nuclear factor kappaB (NF-kappaB) are known to play an important role in pathogenesis of endometrial cancer. However, there is still uncertainty about their proteolytic regulation. We studied the correlation between chymotrypsin-like activity ofproteasomes and IGF-I, IGF-II and NF-kappaB levels in endometrial cancer tissues. The total activity of proteasomes and the 20S and 26S proteasome activities were shown to be significantly higher in malignant tumors than in unaltered endometrium. Negative correlations between the 26S proteasome activity and NF-kappaBp50 level as well as between the 26S and 20S proteasome activities and IGF-I level were found. The data obtained indicate a possible proteasome regulation of growth and transcription factors. As it is considered that the major pool of IGF-I is located in the extracellular space, it is likely that extracellular proteasomes also take part in the regulation of IGF-I content. The positive correlation between IGF-I level and PAPP-A metalloproteinase gives evidence that this proteolytic enzyme is another important regulator of growth factor level, which provides proteolysis of IGF-I binding proteins and increasing IGF-I concentration in tissues. The present data show possibility of proteolytic regulation of growth and nuclear factors that can play an important role in cancer pathogenesis.
Subject(s)
Endometrial Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Insulin-Like Growth Factor II/metabolism , Insulin-Like Growth Factor I/metabolism , NF-kappa B p50 Subunit/metabolism , Proteasome Endopeptidase Complex/metabolism , Case-Control Studies , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Endometrium/metabolism , Endometrium/pathology , Female , Humans , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor II/genetics , Middle Aged , NF-kappa B p50 Subunit/genetics , Neoplasm Staging , Pregnancy-Associated Plasma Protein-A/genetics , Pregnancy-Associated Plasma Protein-A/metabolism , Proteolysis , Signal Transduction/geneticsABSTRACT
Proteasomes (multiproteinase protein complexes) are known to play an important role in cancer pathogenesis, however, few information about their activity in human tumor tissues is available so far. We studied chymotrypsin-like activity of proteasomes in tissues of breast cancer (BC) and endometrial cancer (EC). The chymotrypsin-like total proteasome activity and the 20S and 26S proteasome activity in malignant tissues were shown to be significantly higher in malignant tumors than in normal tissues. No increase in proteasome activity was registered with larger tumor size in both BC and EC, whereas proteasome activity was changed with respect to the extent of tumor involvement. In breast cancer tissues, significant reductions in the total and the 26S proteaome activities were observed in tumors with regional lymph node metastases as compared to tumors without metastases. In endometrial cancer tissues, the total proteasome activity and the 20S and 26S proteasome activities were increased as the depth of myometrial invasion. The data obtained indicate that the proteasome acyivity is significantly changed in the process of cancerogenesis and further study is needed to develop new additional prognostic criteria and effective anti-tumor agents in molecular-directed therapy.
