Purpose: We investigated the mechanisms of how TGF-β pathway is activated by chemotherapeutics and whether a novel TGF-β trap called RER can block chemotherapeutics-induced TGF-β pathway activation and enhance their anti-tumor activity in gynecological cancer. Experimental Design: An unbiased bioinformatic analyses of differentially expressed genes in thirty-one ovarian cases due to chemotherapy was used to identify altered master regulators. Phosphorylated Smad2 was determined in thirty paired cervical cancer using immunohistochemistry. Furthermore, the effects of chemotherapeutics on TGF-β signaling and function, and the effects of RER on chemotherapy-induced TGF-β signaling were determined in gynecological cancer cells. Results: Chemotherapy-induced transcriptome alteration in ovarian cancer was significantly associated with TGF-β signaling activation. Chemotherapy was found to activate TGF-β signaling as indicated by phosphorylated Smad2 in paired cervical tumor samples (pre- and post-chemotherapy). Similar to TGF-β1, chemotherapeutics were found to stimulate Smad2/3 phosphorylation, cell migration, and markers related to epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC). These TGF-β-like effects were due to the stimulation of TGF-β1 expression and secretion, and could all be abrogated by TGF-β inhibitors including a novel TGF-β trap protein called RER both in vitro and in vivo. Importantly, combination treatment with RER and cisplatin showed a higher tumor inhibitory activity than either agent alone in a xenograft model of ovarian cancer. Conclusions: Chemotherapeutics can stimulate TGF-β1 production and consequently enhance TGF-β signaling, EMT, and CSC features resulting in reduced chemo-sensitivity. Combination therapy with a TGF-β inhibitor should alleviate this unintended side effect of chemotherapeutics and enhance their therapeutic efficacy.
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