Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells
Our previous study showed that TPD52 overexpression could increase migration and proliferation of LNCaP cells contributing to the development of prostate cancer. However, mechanism of TPD52 in prostate cancer initiation and progression remains elusive. In this study, we investigated the possible und...
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SAGE Publishing
2017-04-01
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| Series: | Tumor Biology |
| Online Access: | https://doi.org/10.1177/1010428317698382 |
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| author | Chandrashekhar Dasari Dattu Prasad Yaghnam Reinhard Walther Ramesh Ummanni |
| author_facet | Chandrashekhar Dasari Dattu Prasad Yaghnam Reinhard Walther Ramesh Ummanni |
| author_sort | Chandrashekhar Dasari |
| collection | DOAJ |
| description | Our previous study showed that TPD52 overexpression could increase migration and proliferation of LNCaP cells contributing to the development of prostate cancer. However, mechanism of TPD52 in prostate cancer initiation and progression remains elusive. In this study, we investigated the possible underlying mechanism of TPD52 in prostate cancer progression. In LNCaP cells, TPD52 expression was altered by transfecting with either EGFP-TPD52 or specific short hairpin RNA. Overexpression of TPD52 protected LNCaP cells from apoptosis through elevated anti-apoptotic proteins XIAP, Bcl-2, and Cyclin D1, whereas Bax was downregulated. Mechanistically, we found that TPD52 confers transactivation of nuclear factor-κB, thereby enhancing its target gene expression in LNCaP cells. TPD52 promotes LNCaP cell invasion probably via increased matrix metalloproteinase 9 expression and its activity while tissue inhibitor of metalloproteinase expression is significantly downregulated. Notably, TPD52 might be involved in cell adhesion, promoting tumor metastasis by inducing loss of E-cadherin, expression of vimentin and vascular cell adhesion molecule, and additionally activation of focal adhesion kinase. Furthermore, TPD52 directly interacts with nuclear factor-κB p65 (RelA) and promotes accumulation of phosphorylated nuclear factor-κB (p65) S536 that is directly linked with nuclear factor-κB transactivation. Indeed, depletion of TPD52 or inhibition of nuclear factor-κB in TPD52-positive cells inhibited secretion of tumor-related cytokines and contributes to the activation of STAT3, nuclear factor-κB, and Akt. Interestingly, in TPD52 overexpressing LNCaP cells, nuclear factor-κB inhibition prevented the autocrine/paracrine activation of STAT3. TPD52 activates STAT3 through ascertaining a cross talk between the nuclear factor-κB and the STAT3 signaling systems. Collectively, these results reveal mechanism by which TPD52 is associated with prostate cancer progression and highlight the approach for therapeutic targeting of TPD52 in prostate cancer. |
| format | Article |
| id | doaj-art-3498ed650a9640b3bea1b555bf4ccbab |
| institution | OA Journals |
| issn | 1423-0380 |
| language | English |
| publishDate | 2017-04-01 |
| publisher | SAGE Publishing |
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| series | Tumor Biology |
| spelling | doaj-art-3498ed650a9640b3bea1b555bf4ccbab2025-08-20T02:37:33ZengSAGE PublishingTumor Biology1423-03802017-04-013910.1177/1010428317698382Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cellsChandrashekhar Dasari0Dattu Prasad Yaghnam1Reinhard Walther2Ramesh Ummanni3Centre for Academy of Scientific & Innovative Research, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, IndiaCenter for Chemical Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, IndiaDepartment of Medical Biochemistry and Molecular Biology, Ernst Moritz Arndt University of Greifswald, Greifswald, GermanyCenter for Chemical Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, IndiaOur previous study showed that TPD52 overexpression could increase migration and proliferation of LNCaP cells contributing to the development of prostate cancer. However, mechanism of TPD52 in prostate cancer initiation and progression remains elusive. In this study, we investigated the possible underlying mechanism of TPD52 in prostate cancer progression. In LNCaP cells, TPD52 expression was altered by transfecting with either EGFP-TPD52 or specific short hairpin RNA. Overexpression of TPD52 protected LNCaP cells from apoptosis through elevated anti-apoptotic proteins XIAP, Bcl-2, and Cyclin D1, whereas Bax was downregulated. Mechanistically, we found that TPD52 confers transactivation of nuclear factor-κB, thereby enhancing its target gene expression in LNCaP cells. TPD52 promotes LNCaP cell invasion probably via increased matrix metalloproteinase 9 expression and its activity while tissue inhibitor of metalloproteinase expression is significantly downregulated. Notably, TPD52 might be involved in cell adhesion, promoting tumor metastasis by inducing loss of E-cadherin, expression of vimentin and vascular cell adhesion molecule, and additionally activation of focal adhesion kinase. Furthermore, TPD52 directly interacts with nuclear factor-κB p65 (RelA) and promotes accumulation of phosphorylated nuclear factor-κB (p65) S536 that is directly linked with nuclear factor-κB transactivation. Indeed, depletion of TPD52 or inhibition of nuclear factor-κB in TPD52-positive cells inhibited secretion of tumor-related cytokines and contributes to the activation of STAT3, nuclear factor-κB, and Akt. Interestingly, in TPD52 overexpressing LNCaP cells, nuclear factor-κB inhibition prevented the autocrine/paracrine activation of STAT3. TPD52 activates STAT3 through ascertaining a cross talk between the nuclear factor-κB and the STAT3 signaling systems. Collectively, these results reveal mechanism by which TPD52 is associated with prostate cancer progression and highlight the approach for therapeutic targeting of TPD52 in prostate cancer.https://doi.org/10.1177/1010428317698382 |
| spellingShingle | Chandrashekhar Dasari Dattu Prasad Yaghnam Reinhard Walther Ramesh Ummanni Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells Tumor Biology |
| title | Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells |
| title_full | Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells |
| title_fullStr | Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells |
| title_full_unstemmed | Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells |
| title_short | Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells |
| title_sort | tumor protein d52 isoform 3 contributes to prostate cancer cell growth via targeting nuclear factor κb transactivation in lncap cells |
| url | https://doi.org/10.1177/1010428317698382 |
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