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A Novel TGF? Trap Blocks Chemotherapeutics-Induced TGF?1 Signaling and Enhances Their Anticancer Activity in Gynecologic Cancers.

ABSTRACT: Purpose: We investigated the mechanisms of how TGF? pathway is activated by chemotherapeutics and whether a novel TGF? trap called RER can block chemotherapeutics-induced TGF? pathway activation and enhance their antitumor activity in gynecologic cancer.Patients and Methods: An unbiased bioinformatic analysis of differentially expressed genes in 31 ovarian cases due to chemotherapy was used to identify altered master regulators. Phosphorylated Smad2 was determined in 30 paired cervical cancer using IHC. Furthermore, the effects of chemotherapeutics on TGF? signaling and function, and the effects of RER on chemotherapy-induced TGF? signaling were determined in gynecologic cancer cells.Results: Chemotherapy-induced transcriptome alteration in ovarian cancer was significantly associated with TGF? signaling activation. Chemotherapy was found to activate TGF? signaling as indicated by phosphorylated Smad2 in paired cervical tumor samples (pre- and post-chemotherapy). Similar to TGF?1, 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?-like effects were due to the stimulation of TGF?1 expression and secretion, and could all be abrogated by TGF? inhibitors including a novel TGF? 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?1 production and consequently enhance TGF? signaling, EMT, and CSC features resulting in reduced chemo-sensitivity. Combination therapy with a TGF? inhibitor should alleviate this unintended side effect of chemotherapeutics and enhance their therapeutic efficacy. Clin Cancer Res; 24(12); 2780-93. ©2018 AACR.

SUBMITTER: Zhu H

PROVIDER: S-EPMC6004245 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A Novel TGFβ Trap Blocks Chemotherapeutics-Induced TGFβ1 Signaling and Enhances Their Anticancer Activity in Gynecologic Cancers.

Zhu Haiyan H Gu Xiang X Xia Lu L Zhou You Y Bouamar Hakim H Yang Junhua J Ding Xiaofei X Zwieb Christian C Zhang Jianan J Hinck Andrew P AP Sun Lu-Zhe LZ Zhu Xueqiong X

Clinical cancer research : an official journal of the American Association for Cancer Research 20180316 12

<b>Purpose:</b> We investigated the mechanisms of how TGFβ pathway is activated by chemotherapeutics and whether a novel TGFβ trap called RER can block chemotherapeutics-induced TGFβ pathway activation and enhance their antitumor activity in gynecologic cancer.<b>Patients and Methods:</b> An unbiased bioinformatic analysis of differentially expressed genes in 31 ovarian cases due to chemotherapy was used to identify altered master regulators. Phosphorylated Smad2 was determined in 30 paired cerv ...[more]

PMID: 29549162

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Project description:Regulation of transforming growth factor-beta (TGF-beta) signaling is critical in vertebrate development, as several members of the TGF-beta family have been shown to act as morphogens, controlling a variety of cell fate decisions depending on concentration. Little is known about the role of intracellular regulation of the TGF-beta pathway in development. E3 ubiquitin ligases target specific protein substrates for proteasome-mediated degradation, and several are implicated in signaling. We have shown that Arkadia, a nuclear RING-domain E3 ubiquitin ligase, is essential for a subset of Nodal functions in the embryo, but the molecular mechanism of its action in embryonic cells had not been addressed. Here, we find that Arkadia facilitates Nodal signaling broadly in the embryo, and that it is indispensable for cell fates that depend on maximum signaling. Loss of Arkadia in embryonic cells causes nuclear accumulation of phospho-Smad2/3 (P-Smad2/3), the effectors of Nodal signaling; however, these must be repressed or hypoactive as the expression of their direct target genes is reduced or lost. Molecular and functional analysis shows that Arkadia interacts with and ubiquitinates P-Smad2/3 causing their degradation, and that this is via the same domains required for enhancing their activity. Consistent with this dual function, introduction of Arkadia in homozygous null (-/-) embryonic stem cells activates the accumulated and hypoactive P-Smad2/3 at the expense of their abundance. Arkadia-/- cells, like Smad2-/- cells, cannot form foregut and prechordal plate in chimeras, confirming this functional interaction in vivo. As Arkadia overexpression never represses, and in some cells enhances signaling, the degradation of P-Smad2/3 by Arkadia cannot occur prior to their activation in the nucleus. Therefore, Arkadia provides a mechanism for signaling termination at the end of the cascade by coupling degradation of P-Smad2/3 with the activation of target gene transcription. This mechanism can account for achieving efficient and maximum Nodal signaling during embryogenesis and for rapid resetting of target gene promoters allowing cells to respond to dynamic changes in extracellular signals.

Dataset Information

A Novel TGF? Trap Blocks Chemotherapeutics-Induced TGF?1 Signaling and Enhances Their Anticancer Activity in Gynecologic Cancers.

Publications

A Novel TGFβ Trap Blocks Chemotherapeutics-Induced TGFβ1 Signaling and Enhances Their Anticancer Activity in Gynecologic Cancers.

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