Ral GTPase–activating protein regulates the malignancy of pancreatic ductal adenocarcinoma

Shingo Yoshimachi, Ryutaro Shirakawa, Mingxin Cao, Duc Anh Trinh, Pan Gao, Natsumi Sakata, Kento Miyazaki, Kota Goto, Takayuki Miura, Kyohei Ariake, Shimpei Maeda, Kunihiro Masuda, Masaharu Ishida, Hideo Ohtsuka, Michiaki Unno, Hisanori Horiuchi

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

The small GTPases RalA and RalB are members of the Ras family and activated downstream of Ras. Ral proteins are found in GTP-bound active and GDP-bound inactive forms. The activation process is executed by guanine nucleotide exchange factors, while inactivation is mediated by GTPase-activating proteins (GAPs). RalGAPs are complexes that consist of a catalytic α1 or α2 subunit together with a common β subunit. Several reports implicate the importance of Ral in pancreatic ductal adenocarcinoma (PDAC). However, there are few reports on the relationship between levels of RalGAP expression and malignancy in PDAC. We generated RalGAPβ-deficient PDAC cells by CRISPR-Cas9 genome editing to investigate how increased Ral activity affects malignant phenotypes of PDAC cells. RalGAPβ-deficient PDAC cells exhibited several-fold higher Ral activity relative to control cells. They had a high migratory and invasive capacity. The RalGAPβ-deficient cells grew more rapidly than control cells when injected subcutaneously into nude mice. When injected into the spleen, the RalGAPβ-deficient cells formed larger splenic tumors with more liver metastases, and unlike controls, they disseminated into the abdominal cavity. These results indicate that RalGAPβ deficiency in PDAC cells contributes to high activities of RalA and RalB, leading to enhanced cell migration and invasion in vitro, and tumor growth and metastasis in vivo.

Original languageEnglish
Pages (from-to)3064-3073
Number of pages10
JournalCancer science
Volume112
Issue number8
DOIs
Publication statusPublished - 2021 Aug

Keywords

  • Ral
  • RalGAP
  • Ras
  • pancreatic ductal adenocarcinoma
  • small GTPase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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