5Z-7-Oxozeanol Inhibits the Effects of TGFβ1 on Human Gingival Fibroblasts

Abstract

Transforming growth factor (TGF)β acts on fibroblasts to promote the production and remodeling of extracellular matrix (ECM). In adult humans, excessive action of TGFβ is associated with fibrotic disease and fibroproliferative conditions, including gingival hyperplasia. Understanding how the TGFβ1 signals in fibroblasts is therefore likely to result in valuable insights into the fundamental mechanisms underlying fibroproliferative disorders. Previously, we used the TAK1 inhibitor (5Z)-7-Oxozeaenol to show that, in dermal fibroblasts, the non-canonical TAK1 pathway mediates the ability of TGFβ1 to induce genes promoting tissue remodeling and repair. However, the extent to which TAK1 mediates fibroproliferative responses in fibroblasts in response to TGFβ1 remains unclear. Herein, we show that, in gingival fibroblasts, (5Z)-7-Oxozeaenol blocks the ability of TGFβ1 to induce expression of the pro-fibrotic mediator CCN2 (connective tissue growth factor, CTGF) and type I collagen protein. Moreover, genome-wide expression profiling revealed that, in gingival fibroblasts, (5Z)-7-Oxozeaenol reduces the ability of TGFβ1 to induce mRNA expression of essentially all TGFβ1-responsive genes (139/147), including those involved with a hyperproliferative response. Results from microarray analysis were confirmed using real time polymerase chain reaction analysis and a functional cell proliferation assay. Our results are consistent with the hypothesis that TAK1 inhibitors might be useful in treating fibroproliferative disorders, including that in the oral cavity.

Antioxidants and NOX1/NOX4 inhibition blocks TGFβ1-induced CCN2 and α-SMA expression in dermal and gingival fibroblasts

“…Previously, we showed that TGFβ-induced CCN2 expression in HDF and HFF was blocked by focal adhesion kinase (FAK) or TGFβ-activated kinase 1 (TAK1) inhibition [ 8 , 11 , 23 , 24 ]. To further explore the underlying involvement of NOX enzymes in the induction of fibrogenic responses in fibroblasts, we assessed if the inhibition of FAK and TAK1 would potentially block TGFβ1-induced NOX4 expression.…”

“…It is interesting to note that prior reports indicated, in fibroblasts, TAK1 and FAK mediate collagen expression including in response to TGFβ1 [ 11 , 23 , 24 ]. Moreover, NAC reduced type I collagen expression in SSc fibroblasts [ 11 ]; however, in this study NAC did not appreciably affect TGFβ1-induced COL1A1 expression.…”

Yin/Yang expression of CCN family members: Transforming growth factor beta 1, via ALK5/FAK/MEK, induces CCN1 and CCN2, yet suppresses CCN3, expression in human dermal fibroblasts

“…Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1 (TGFbeta-activated kinase 1), once activated, is an upstream activator of MKK/JNK and p38 by the phosphorylation and activation of MAP kinase kinases such as MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. TAK1 deletion blocks TGFbeta-induced alpha-smooth muscle actin expression in mouse embryonic fibroblasts, and, in gingival fibroblasts, the TAK1 inhibitor (5Z)-7-Oxozeaenol blocks the ability of TGFbeta1 to induce CCN2 expression [42,43]. To extend these studies, we assessed the ability of (5Z)-7-Oxozeaenol to block the effect of TGFbeta1 on CCN1, CCN2 and CCN3 expression in human dermal fibroblasts.…”

TAK1 inhibitor 5Z-7-oxozeaenol sensitizes cervical cancer to doxorubicin-induced apoptosis

“…5Z-7, is a novel TAK1 inhibitor that has been studied in lymphoma [38], neuroblastoma [37], fibroblasts [44] and breast cancer [45]. A closely related analog of 5Z-7, termed E6201, is in phase II clinical trials by Eisai Inc., for the treatment of melanoma, as well as being a possible topical agent for treatment of psoriasis [45].…”