Ral GTPase promotes metastasis of pancreatic ductal adenocarcinoma via elevation of TGF-β1 production

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

doi:10.1016/j.jbc.2023.104754

Ral GTPase promotes metastasis of pancreatic ductal adenocarcinoma via elevation of TGF-β1 production

J Biol Chem. 2023 Jun;299(6):104754. doi: 10.1016/j.jbc.2023.104754. Epub 2023 Apr 26.

Authors

Affiliations

¹ Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan; Department of Oral Cancer Therapeutics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan; State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China; School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China.
² Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin Stomatological Hospital, The Affiliated Stomatological Hospital of Nankai University, Tianjin, China.
³ Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan.
⁴ Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan; Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
⁵ Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
⁶ Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan. Electronic address: ryutaro.shirakawa.b1@tohoku.ac.jp.
⁷ Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan; Department of Oral Cancer Therapeutics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan. Electronic address: hisanori.horiuchi.e8@tohoku.ac.jp.

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.

Keywords: Ral GTPase; RalGAP; TGF-β1; metastasis; pancreatic ductal adenocarcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Pancreatic Ductal* / metabolism
Cell Line, Tumor
Cell Movement
GTP Phosphohydrolases / metabolism
Gene Expression Regulation, Neoplastic
Humans
Mice
Neoplasm Metastasis
Pancreatic Neoplasms* / pathology
Transforming Growth Factor beta1* / metabolism

Substances

GTP Phosphohydrolases
Transforming Growth Factor beta1