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Abstract

The present study investigated the modulatory role of transforming growth factor beta 1 (TGFbeta1) on the secretion of matrix metalloproteinases (MMPs) and tested whether the altered secretion of MMPs could directly affect the invasive behavior of ovarian cancer cells. To this aim, human ovarian cancer SKOV3 cells were treated once with vehicle or various concentrations of TGFbeta1 for 24 h. Gelatinase activities in conditioned media were analyzed by zymography and densitometry. TGFbeta1 dose-dependently stimulated the secretion of a 68-kDa gelatinase, which was characterized as an MMP because its activity was inhibited by a metalloproteinase inhibitor 1,10-phenanthroline, and by a synthetic MMP inhibitor BB3103. In addition, we used aminophenylmercuric acetate (APMA) to activate latent gelatinases. APMA time-dependently decreased the activity of 68-kDa gelatinase, and increased the activities of 64- and 62-kDa gelatinolytic bands. The 68-kDa gelatinase was further characterized as MMP2 (gelatinase A) by immunoblotting analysis. We then tested TGFbeta1 effect on the invasive potential of SKOV3 cells as assessed by the migration ability through reconstituted basement membrane, and further investigated whether TGFbeta1 may act through modulating the MMP activity to affect ovarian cancer cell invasion. The results show that TGFbeta1 stimulated the invasive behavior of SKOV3 cells, and that MMP inhibitor BB3103 abrogated this effect of TGFbeta1. In conclusion, this study indicates that TGFbeta1 may act partly through stimulating the secretion of MMP in promoting the invasive behavior of human ovarian cancer cells. Furthermore, this work supports the idea that specific MMP inhibitors of the hydroxamate class could be therapeutically useful in controlling cancer cell invasion/metastasis.

Melatonin Reduces Angiogenesis in Serous Papillary Ovarian Carcinoma of Ethanol-Preferring Rats

“…Furthermore, TGF-β1 stimulates matrix metalloproteinase secretion, thereby promoting OC cell invasion [39]. Several clinical studies report that TGF-β1 and TGF-β1-binding protein mRNAs are elevated in OC tissue and in ascites fluid [19,40].…”

A potential anti-tumor herbal medicine, Corilagin, inhibits ovarian cancer cell growth through blocking the TGF-β signaling pathways

“…Much remains to be elucidated about how TGF-β contributes to ovarian cancer progression, particularly in the regulation of EMT. A high concentration of TGF-β has been detected in ascites, blood and other bodily fluids of ovarian cancer patients [22]. When ovarian cancer cells were cultured, various TGF-βs, including TGF-β1, TGF-β2 and TGF-β3, induced pro-matrix metalloproteinase (MMP) secretion, the loss of cell-cell junctions, down-regulation of E-cadherin, up-regulation of N-cadherin, and the acquisition of a fibroblastoid phenotype, all of which are consistent with EMT [23-25].…”

A Novel Mechanism of PPARγ Regulation of TGFβ1: Implication in Cancer Biology

“…Several lines of evidence also support the concept that TGF β -induced Smad signaling is responsible for the invasiveness of cancer cells [55–58]. This is explained in part by the TGF β -dependent induction of matrix metalloproteases, which are known to be responsible for cell migration and invasion [55, 59–62]. Activation of ERK and JNK by TGF β and their association with focal complexes may also contribute to cell migration, as shown in the case of breast carcinoma [63].…”