Matrix metalloproteinase-9 Inhibition Down-Regulates Radiation-Induced Nuclear Factor-κB Activity Leading to Apoptosis in Breast Tumors

Kunigal, Sateesh; Lakka, Seeta S.; Joseph, Pushpa A.; Estes, Norman C.; Rao, Jasti S.

doi:10.1158/1078-0432.ccr-07-2060

Cited by 30 publications

(28 citation statements)

References 44 publications

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“…Several reports have shown that Fas/Fasligand system is enhanced in the cancer cells treated with anti-cancer chemotherapeutic agents 57. Apart from chemotherapeutic agents, down regulation of MMPs was reported to induce Fas-mediated apoptosis and inhibit tumor progression in lung cancer58 and breast cancer 59. Similarly, in the present study the expressions of Fas-ligand as well as its receptor were enhanced in the siRNA plasmid transfected prostate cancer cells, providing further insight to the earlier reports.…”

Section: Discussionsupporting

confidence: 87%

Targeting MMP-9, uPAR, and cathepsin B inhibits invasion, migration and activates apoptosis in prostate cancer cells

et al. 2010

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Prostate cancer is one of the most commonly diagnosed cancers and the second leading cause of cancer deaths in Americans. The high mortality rate is mainly attributed to the invasiveness and metastasis of advanced prostate cancer. Targeting the molecules involved in metastasis could be an effective mode of treatment for prostate cancer. In this study, the therapeutic potential of siRNAmediated targeting of matrix metalloproteinase-9 (MMP-9), urokinase plasminogen activator receptor (uPAR), and cathepsin B (CB) in prostate cancer was carried out using single and bi-cistronic siRNA-expressing constructs. Downregulation of MMP-9, uPAR, and CB inhibited matrigel invasion, in vitro angiogenesis and wound-healing migration ability of PC3 and DU145 prostate cancer cell lines. In addition, the siRNA treatments induced apoptosis in the tumor cells as determined by TUNEL and DNA laddering assays. An attempt to elucidate the apoptotic pathway showed the involvement of FAS-mediated activation of caspases-8 and -7. Further, mice with orthotopic prostate tumors treated with siRNA-expressing vectors showed significant inhibition in tumor growth and migration. In conclusion, we report that the siRNA-mediated knockdown of MMP-9, uPAR, and CB inhibits invasiveness and migration of prostate cancer cells and leads to apoptosis both in vitro and in vivo.

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Section: Discussionsupporting

confidence: 87%

Targeting MMP-9, uPAR, and cathepsin B inhibits invasion, migration and activates apoptosis in prostate cancer cells

et al. 2010

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“…The over expression of uPA, uPAR and cathepsin B by radiation has been detected in various malignancies, including those in hepatocellular [22], rectal [23] and breast [24] cancer. Most of the cellular responses modulated by these proteolytic networks, including migration, cellular adhesion, differentiation, proliferation and angiogenesis require transmembrane signaling, which is mediated by direct contacts of these proteolytic networks with a variety of extracellular proteins and membrane receptors.…”

Section: Discussionmentioning

confidence: 99%

uPAR/Cathepsin B Overexpression Reverse Angiogenesis by Rescuing FAK Phosphorylation in uPAR/Cathepsin B Down Regulated Meningioma

et al. 2011

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BackgroundMeningiomas are the most commonly occurring intracranial tumors and account for approximately 15−20% of central nervous system tumors. Surgery and radiation therapy is a common treatment for brain tumors, however, patients whose tumors recur after such treatments have limited therapeutic options. Earlier studies have reported important roles of uPA, uPAR and cathepsin B in tumor progression.Methodology/Principal FindingsIn the present study, we examined the therapeutic significance of RNAi-mediated simultaneous down regulation of these proteolytic networks using two bicistronic siRNA constructs, pUC (uPAR/cathepsin B) and pU2 (uPA/uPAR) either alone or in combination with radiation in two different meningioma cell lines. Transfection of meningioma cells with pUC and pU2 significantly reduced angiogenesis as compared to control treatment both in vitro and in vivo nude mice model. This effect is mediated by inhibiting angiogenic molecules (Ang-1, Ang-2 and VEGF). Expression of focal adhesion kinase (FAK) is elevated in malignant meningioma, yet the role of intrinsic FAK activity in promoting tumor progression remains undefined. We found that pUC treatment reduced FAK phosphorylation at Y925 more efficiently compared to pU2 treatment. In immunoprecipitation assay, we found pronounced reduction of FAK (Y925) interaction with Grb2 in meningioma cells transfected with pUC with and without irradiation. Transient over-expression of uPAR and cathepsin B by full length uPAR/cathepsin B (FLpU/C) in pUC transfected meningioma cells promoted vascular phenotype, rescued expression of Ang-1, Ang-2, VEGF, FAK (Y925) and Grb2 both in vitro and in vivo mice model.Conclusion/SignificanceThese studies provide the first direct proof that bicistronic siRNA construct for uPAR and cathepsin B (pUC) reduces Y925-FAK activity and this inhibition is rescued by overexpression of both uPAR and cathepsin B which clearly demonstrates that pUC could thus be a potential therapeutic approach as an anti-angiogenic agent in meningioma.

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“…HGF induces VEGF expression in cancer cells and is a key switch for turning on angiogenesis [61]. It has been reported that adenovirus-mediated inhibition of MMP-9 (Ad-MMP-9) with radiotherapy decreased levels of NF-κB and activator protein 1, both of which contribute to the radioresistance of MDA-MB-231 cells in vitro and in vivo ; treatment with Ad-MMP-9 plus radiation completely regressed tumor growth in orthotopic breast cancer model [62]. Our present results of reduction of MMP-9 in the radiotherapy patients who received EGCG may contribute to the decrease in NF-κB level and inhibition of proliferation in breast cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Anti-Cancer Activities of Tea Epigallocatechin-3-Gallate in Breast Cancer Patients under Radiotherapy

Zhang

Wang

Zhang

et al. 2012

CMM

147

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The purpose of this study was to test the hypothesis that administration of epigallocatechin-3-gallate (EGCG), a polyphenol present in abundance in widely consumed tea, inhibits cell proliferation, invasion, and angiogenesis in breast cancer patients. EGCG in 400 mg capsules was orally administered three times daily to breast cancer patients undergoing treatment with radiotherapy. Parameters related to cell proliferation, invasion, and angiogenesis were analyzed while blood samples were collected at different time points to determine efficacy of the EGCG treatment. Compared to patients who received radiotherapy alone, those given radiotherapy plus EGCG for an extended time period (two to eight weeks) showed significantly lower serum levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and reduced activation of metalloproteinase-9 and metalloproteinase-2 (MMP9/MMP2). Addition of sera obtained from patients treated with combination of radiotherapy and EGCG feeding for 2–8 weeks to in vitro cultures of highly-metastatic human MDA-MB-231 breast cancer cells resulted in the following significant changes: (1) suppression of cell proliferation and invasion; (2) arrest of cell cycles at the G0/G1 phase; (3) reduction of activation of MMP9/MMP2, expressions of Bcl-2/Bax, c-Met receptor, NF-κB, and the phosphorylation of Akt. MDA-MB-231 cells exposed to 5–10 µM EGCG also showed significant augmentation of the apoptosis inducing effects of γ-radiation, concomitant with reduced NF-κB protein level and AKT phosphorylation. These results provide hitherto unreported evidence that EGCG potentiated efficacy of radiotherapy in breast cancer patients, and raise the possibility that this tea polyphenol has potential to be a therapeutic adjuvant against human metastatic breast cancer.

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Matrix metalloproteinase-9 Inhibition Down-Regulates Radiation-Induced Nuclear Factor-κB Activity Leading to Apoptosis in Breast Tumors

Cited by 30 publications

References 44 publications

Targeting MMP-9, uPAR, and cathepsin B inhibits invasion, migration and activates apoptosis in prostate cancer cells

Targeting MMP-9, uPAR, and cathepsin B inhibits invasion, migration and activates apoptosis in prostate cancer cells

uPAR/Cathepsin B Overexpression Reverse Angiogenesis by Rescuing FAK Phosphorylation in uPAR/Cathepsin B Down Regulated Meningioma

Anti-Cancer Activities of Tea Epigallocatechin-3-Gallate in Breast Cancer Patients under Radiotherapy

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