Ral GTPase promotes metastasis of pancreatic ductal adenocarcinoma via elevation of TGF-β1 production.
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| Abstract |
Pancreatic ductal adenocarcinoma (PDAC), caused by activating mutations in K-Ras, is an aggressive malignancy due to its early invasion and metastasis. Ral GTPases are activated downstream of Ras and play a crucial role in the development and progression of PDAC. However, the underlying mechanisms remain unclear. In this study, we investigated the mechanism of Ral-induced invasion and metastasis of PDAC cells using RalGAPβ-deficient PDAC cells with highly activated Ral GTPases. Array analysis and ELISA revealed increased expression and secretion of TGF-β1 in RalGAPβ-deficient PDAC cells compared to control cells. Blockade of TGF-β1 signaling suppressed RalGAPβ deficiency-enhanced migration and invasion in vitro and metastasis in vivo to levels similar to controls. Phosphorylation of c-Jun N-terminal kinase, a repressor of TGF-β1 expression, was decreased by RalGAPβ deficiency. These results indicate that Ral contributes to invasion and metastasis of PDAC cells by elevating autocrine TGF-β1 signaling at least in part by decreasing c-Jun N-terminal kinase activity.
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| Authors | Mingxin Cao, Xinming Li, Duc-Anh Trinh, Shingo Yoshimachi, Kota Goto, Natsumi Sakata, Masaharu Ishida, Hideo Ohtsuka, Michiaki Unno, Yuxia Wang, Ryutaro Shirakawa, Hisanori Horiuchi |
| Journal | The Journal of biological chemistry (J Biol Chem) Vol. 299 Issue 6 Pg. 104754 (06 2023) ISSN: 1083-351X [Electronic] United States |
| PMID | 37116704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. |
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