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Tissue Inhibitor of Metalloproteinase-4 Triggers Apoptosis in Cervical Cancer Cells.

Lizarraga F, Ceballos-Cancino G, Espinosa M, Vazquez-Santillan K, Maldonado V, Melendez-Zajgla J - PLoS ONE (2015)

Bottom Line: We showed that TIMP-4 has apoptosis-sensitizing effects towards several death stimuli.In addition, TIMP-4 knockdown resulted in cell survival increase after serum deprivation, as assessed by clonogenic cell analyses.Understanding TIMP-4 effects in tumorigenesis may provide clues for future therapies.

View Article: PubMed Central - PubMed

Affiliation: Basic Research Subdivision, National Institute of Genomic Medicine, Functional Genomics Laboratory, Periferico Sur 4809, Col. Arenal Tepepan, Del. Tlalpan. Mexico, D.F. C.P.14610, Mexico.

ABSTRACT
Tissue inhibitor of metalloproteinase-4 (TIMP-4) is a member of extracellular matrix (ECM) metalloproteinases inhibitors that has pleiotropic functions. However, TIMP-4 roles in carcinogenesis are not well understood. Cell viability and flow cytometer assays were employed to evaluate cell death differences between H-Vector and H-TIMP-4 cell lines. Immunobloting and semi-quantitative RT-PCR were used to evaluate the expression of apoptosis regulators. We showed that TIMP-4 has apoptosis-sensitizing effects towards several death stimuli. Consistent with these findings, regulators of apoptosis from Inhibitors of Apoptosis Proteins (IAP), FLICE-like inhibitor proteins (FLIP) and Bcl-2 family members were modulated by TIMP-4. In addition, TIMP-4 knockdown resulted in cell survival increase after serum deprivation, as assessed by clonogenic cell analyses. This report shows that TIMP-4 regulates carcinogenesis through apoptosis activation in cervical cancer cells. Understanding TIMP-4 effects in tumorigenesis may provide clues for future therapies.

No MeSH data available.


Related in: MedlinePlus

TIMP-4 induces cell death in vitro.A, TIMP-4 modulates TNFRI, TNFRII and DISC components TRAF2 and TRADD. Proteins were detected by immunoblot in H-Vector and H-TIMP-4 cells protein extracts.
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pone.0135929.g005: TIMP-4 induces cell death in vitro.A, TIMP-4 modulates TNFRI, TNFRII and DISC components TRAF2 and TRADD. Proteins were detected by immunoblot in H-Vector and H-TIMP-4 cells protein extracts.

Mentions: Recently, it has been shown that TIMP-3, a potent inducer of apoptosis, promotes death in melanoma cells through the stabilization of death receptors and consequent activation of their apoptotic-signaling cascade through caspase-8 [14]. Because we observed caspase-8 cleavage products in H-TIMP-4 cells upon TNF-α stimulation (Fig 2C), we assessed the protein levels of TNFRI, RII, and the DISC components TRAF2 and TRADD. As shown in Fig 5A, we observed a decrease in TNFRI, TRADD, and TRAF2 protein levels in H-TIMP-4 cells, while TNFRII levels were unchanged. Altogether, these results showed that TIMP-4 sensitizes HeLa cells to apoptosis in vitro by altering the balance of key apoptotic players in support of cell death.


Tissue Inhibitor of Metalloproteinase-4 Triggers Apoptosis in Cervical Cancer Cells.

Lizarraga F, Ceballos-Cancino G, Espinosa M, Vazquez-Santillan K, Maldonado V, Melendez-Zajgla J - PLoS ONE (2015)

TIMP-4 induces cell death in vitro.A, TIMP-4 modulates TNFRI, TNFRII and DISC components TRAF2 and TRADD. Proteins were detected by immunoblot in H-Vector and H-TIMP-4 cells protein extracts.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4546159&req=5

pone.0135929.g005: TIMP-4 induces cell death in vitro.A, TIMP-4 modulates TNFRI, TNFRII and DISC components TRAF2 and TRADD. Proteins were detected by immunoblot in H-Vector and H-TIMP-4 cells protein extracts.
Mentions: Recently, it has been shown that TIMP-3, a potent inducer of apoptosis, promotes death in melanoma cells through the stabilization of death receptors and consequent activation of their apoptotic-signaling cascade through caspase-8 [14]. Because we observed caspase-8 cleavage products in H-TIMP-4 cells upon TNF-α stimulation (Fig 2C), we assessed the protein levels of TNFRI, RII, and the DISC components TRAF2 and TRADD. As shown in Fig 5A, we observed a decrease in TNFRI, TRADD, and TRAF2 protein levels in H-TIMP-4 cells, while TNFRII levels were unchanged. Altogether, these results showed that TIMP-4 sensitizes HeLa cells to apoptosis in vitro by altering the balance of key apoptotic players in support of cell death.

Bottom Line: We showed that TIMP-4 has apoptosis-sensitizing effects towards several death stimuli.In addition, TIMP-4 knockdown resulted in cell survival increase after serum deprivation, as assessed by clonogenic cell analyses.Understanding TIMP-4 effects in tumorigenesis may provide clues for future therapies.

View Article: PubMed Central - PubMed

Affiliation: Basic Research Subdivision, National Institute of Genomic Medicine, Functional Genomics Laboratory, Periferico Sur 4809, Col. Arenal Tepepan, Del. Tlalpan. Mexico, D.F. C.P.14610, Mexico.

ABSTRACT
Tissue inhibitor of metalloproteinase-4 (TIMP-4) is a member of extracellular matrix (ECM) metalloproteinases inhibitors that has pleiotropic functions. However, TIMP-4 roles in carcinogenesis are not well understood. Cell viability and flow cytometer assays were employed to evaluate cell death differences between H-Vector and H-TIMP-4 cell lines. Immunobloting and semi-quantitative RT-PCR were used to evaluate the expression of apoptosis regulators. We showed that TIMP-4 has apoptosis-sensitizing effects towards several death stimuli. Consistent with these findings, regulators of apoptosis from Inhibitors of Apoptosis Proteins (IAP), FLICE-like inhibitor proteins (FLIP) and Bcl-2 family members were modulated by TIMP-4. In addition, TIMP-4 knockdown resulted in cell survival increase after serum deprivation, as assessed by clonogenic cell analyses. This report shows that TIMP-4 regulates carcinogenesis through apoptosis activation in cervical cancer cells. Understanding TIMP-4 effects in tumorigenesis may provide clues for future therapies.

No MeSH data available.


Related in: MedlinePlus