NFκB signalling is upregulated in a subset of castrate-resistant prostate cancer patients and correlates with disease progression

McCall, Pamela; Bennett, Louise; Ahmad, Imran; Mackenzie, Lewis; Forbes, I W G; Leung, Hing Y.; Sansom, O.; Orange, Clare; Seywright, Morag; Underwood, M.A.; Edwards, Joanne

doi:10.1038/bjc.2012.372

Cited by 61 publications

(53 citation statements)

References 28 publications

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“…7 Activated NF-κB is associated with PCa progression through MMP expression and/or activation or inducing androgen independence. 50 Interestingly, our results in this study implicate that overexpression of TPD52 induces expression and activity of MMP-9 in LNCaP cells. TIMPs will regulate intracellular activity of MMPs, and there are four TIMP family members, including TIMP-1, TIMP-2, TIMP-3, and TIMP-4.…”

Section: Discussionmentioning

confidence: 57%

Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 57%

Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells

et al. 2017

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“…Increased activation of NF-kB signaling through proinflammatory stimuli in tumor microenvironment has been demonstrated to stimulate proliferation, migration and metastasis of cancer cells and inhibit apoptosis in many human malignancies including prostate cancer [20,23,24]. More importantly, in breast cancer patients NF-kB activation promoted up-regulation of MMP-9 which was closely associated with shorter lifespan [25].…”

Section: Introductionmentioning

confidence: 94%

“…More importantly, in breast cancer patients NF-kB activation promoted up-regulation of MMP-9 which was closely associated with shorter lifespan [25]. All of the studies related to the NF-kB-dependent-MMP regulation in prostate cancer focused on the regulation of gelatinases (MMP-2 and -9) [23,26]. However, the role of NF-kB activation in the gene regulation of MMPs from the subgroups of collagenases and stromelysins in prostate cancer has not been studied yet.…”

Section: Introductionmentioning

confidence: 99%

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Doxycycline down-regulates matrix metalloproteinase expression and inhibits NF-κB signaling in LPS-induced PC3 cells

Ogut

Reel

Korkmaz

et al. 2017

Folia Histochem Cytobiol.

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Introduction. Matrix metalloproteinase enzymes (MMPs) play important role in inflammation, malignant cell proliferation, invasion and angiogenesis by mediating extracellular matrix degradation. Doxycycline, a synthetic tetracycline, behaves as a MMP inhibitor at a subantimicrobial dose and inhibits tumor cell proliferation, invasion and angiogenesis. The aberrant activity of nuclear factor kappa B (NF-kB) causes activation of MMPs and thereby proliferation and invasion of cancer cells. The aim of this study was to investigate the effects of doxycycline on the expression of MMPs in lipopolysaccharide (LPS)-induced PC3 human prostate cancer cells and the possible role of NF-kB signaling. Material and methods. PC3 cells were incubated with LPS (0.5 µg/mL) for 24 h in the presence or absence of doxycycline (5 µg/mL). The effects of LPS and doxycycline on the expressions of MMP-2, MMP-8, MMP-9, MMP-10, NF-kB/p65, IkB-a, p-IkB-a, IKK-b were examined by Western blotting and immunohistochemistry in PC3 cells. Furthermore, relative proteinase activities of MMP-2 and MMP-9 were determined by gelatin zymography. Results. LPS increased expression and activity of MMP-9 and expression of MMP-8, MMP-10, NF-kB/p65, p-IkB-a, IKK-b and doxycycline down-regulated its effects with the exception of MMP-10 expression. The expression of MMP-2 and IkB-a was affected by neither LPS nor doxycycline. Conclusions. Our findings indicate that doxycycline inhibits the expression of various MMPs and NF-kB signaling may play a role in the regulation of MMPs expression in LPS-induced PC3 human prostate cancer cells.

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“…NF-κB transcription factors regulate a variety of immune and inflammatory responses and developmental processes (reviewed by [82]). Levels of NF-κB correlate with prognosis in PC patients, and increased NF-κB signaling correlates with disease progression in a subset of PC patients [83]. NF-κB regulates EMT by directly or indirectly upregulating multiple EMT transcription factors, the mesenchymal intermediate filament protein vimentin, and matrix metalloproteases MMP2 and MMP9 [84].…”

Section: Ptenmentioning

confidence: 99%

Development of a Novel Method to Detect Prostate Cancer Circulating Tumor Cells (CTCs) Based on Epithelial-Mesenchymal Transition Biology

Armstrong¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE December 2014 REPORT TYPE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Duke University Medical Durham, NC 27705 AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe purpose of this DOD NIA is to develop a novel method to detect circulating tumor cells (CTCs) from men with metastatic castration resistant prostate cancer (CRPC) based on a range of CTC phenotypes. The novel method employs a nanoparticle polymersome that contains near-infrared emissive porphyrins and permits antibody conjugation for target engagement and flow sorting in the infrared spectrum for specificity. We are developing near infrared emissive polymersomes (NIR-EPs) that contain antibodies to EpCAM, N-cadherin, OB-cadherin, and PSMA which permit the isolation and enumeration ev vivo of CTCs bearing these antigens in the circulation of men with CRPC. These specialized CTC detection nanoparticles permit the isolation of specific CTC phenotypes including epithelial, mesenchymal, and prostate cancer specific targets. In year 2 we have continued to optimize the methodology and chemistry for the creation of these NIR-EPs, including chemical synthesis, antibody conjugation, optimal reagents and processing, positive and negative control cell applications, and methods for red cell lysis, leukocyte depletion, and flow sorting of CTCs in the infrared spectrum. Challenges have included specificity due to antibody affinity during conjugation. This work is ongoing in the Therien laboratory to provide a clinical reagent for the ex vivo capture and identification of CTCs without binding to leukocytes nonspecifically. A 6 month no cost extension was requested to continue this optimization process. 2 Many patients with metastatic PC, however, have undetectable CTCs, limiting clinical utility. We have identified epithelial-mesench...

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NFκB signalling is upregulated in a subset of castrate-resistant prostate cancer patients and correlates with disease progression

Cited by 61 publications

References 28 publications

Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells

Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells

Doxycycline down-regulates matrix metalloproteinase expression and inhibits NF-κB signaling in LPS-induced PC3 cells

Development of a Novel Method to Detect Prostate Cancer Circulating Tumor Cells (CTCs) Based on Epithelial-Mesenchymal Transition Biology

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