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G3BP2 promotes tumor progression and gemcitabine resistance in PDAC via regulating PDIA3-DKC1-hENT in a stress granules-dependent manner

Acta Pharmacologica Sinica volume 46, pages 474–488 (2025)Cite this article

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is distinguished by its aggressive malignancy, limited treatment avenues and a tendency towards chemotherapy resistance, underscoring the critical need for advanced research to uncover new therapeutic approaches. Stress granules (SGs) that is implicated in cellular self-protection mechanism, along with its associated family molecules have shown pro-cancer effects and are closely related to tumor chemotherapy resistance. In this study we investigated the relationship between Ras GTPase-activating protein-binding proteins 2 (G3BP2), a core component of SGs, and the malignancy of PDAC as well as its resistance to the chemotherapy drug gemcitabine. Analyzing TCGA dataset revealed that the expression of G3BP1 and G3BP2 was significantly upregulated in PDAC compared with adjacent normal pancreatic tissues, and the high expression of G3BP2 rather than G3BP1 was significantly associated with poorer overall survival (OS) in PDAC patients. We demonstrated that knockdown of G3BP2 inhibited the proliferation and invasion of PANC‐1 and CFPAC-1 cells in vitro and in vivo. By analyzing the differentially expressed genes in G3BP2 knockdown and overexpressed PANC‐1 cells, we identified DKC1 that was associated with RNA stability and regulation as the target of G3BP2. We demonstrated that G3BP2 bound to PDIA3 mRNA and recruited them into SGs, increasing the stability of PDIA3 mRNA and attenuating its translation efficiency, thereby promoting DKC1 expression. Furthermore, DKC1 could bind to hENT mRNA and inhibited its expression, which enhanced gemcitabine resistance of PDAC. Therefore, we propose a novel mechanism wherein G3BP2 facilitates PDAC’s resistance to chemotherapy by modulating PDIA3-DKC1-hENT in a SGs-dependent way, suggesting G3BP2 SGs a protentional therapeutic target for the treatment in PDAC.

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Fig. 1: G3BP2 is significantly upregulated and indicates a worse prognosis in PDAC patients.
Fig. 2: Knockdown of G3BP2 inhibits PDAC proliferation and invasion in vitro and vivo.
Fig. 3: G3BP2 promotes PDAC gemcitabine resistance in a SGs-dependent manner.
Fig. 4: RNA profile indicates tumor-promotive role of G3BP2 could be related to DKC1.
Fig. 5: G3BP2 regulated DKC1 expression by binding to PDIA3 mRNAs and shuttling them into SGs.
Fig. 6: Knockdown of DKC1 blocks the tumor-promotive effect of G3BP2.
Fig. 7: DKC1 increased hENT mRNA stability and reduced the translation of hENT mRNA.
Fig. 8: C108 synergistically promotes anti-tumor roles of gemcitabine.
Fig. 9

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Acknowledgements

This study was jointly supported by the National Natural Science Foundation of China (82173178, 82173281, U21A20374, and 82072698), Shanghai Municipal Science and Technology Major Project (21JC1401500), Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057), Natural Science Foundation of Shanghai Municipal Science and Technology Committee (21ZR1415200) and Natural Science Foundation of Shanghai (23ZR1479300).

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Author notes

  1. These authors contributed equally: Fa-liang Xing, Bo-rui Li, Ying-jin Fang

Authors and Affiliations

  1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Fa-liang Xing, Bo-rui Li, Ying-jin Fang, Chen Liang, Jiang Liu, Wei Wang, Jin Xu, Xian-jun Yu, Yi Qin & Bo Zhang

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Fa-liang Xing, Bo-rui Li, Ying-jin Fang, Chen Liang, Jiang Liu, Wei Wang, Jin Xu, Xian-jun Yu, Yi Qin & Bo Zhang

  3. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China

    Fa-liang Xing, Bo-rui Li, Ying-jin Fang, Chen Liang, Jiang Liu, Wei Wang, Jin Xu, Xian-jun Yu, Yi Qin & Bo Zhang

  4. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China

    Fa-liang Xing, Bo-rui Li, Ying-jin Fang, Chen Liang, Jiang Liu, Wei Wang, Jin Xu, Xian-jun Yu, Yi Qin & Bo Zhang

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Contributions

BZ, YQ, XJY, JX and WW designed research; FLX and BRL performed research; FLX, YJF, CL and JL contributed new analytical tools and reagents; FLX, BRL and YJF analyzed data; FLX wrote the paper.

Corresponding authors

Correspondence to Xian-jun Yu, Yi Qin or Bo Zhang.

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Xing, Fl., Li, Br., Fang, Yj. et al. G3BP2 promotes tumor progression and gemcitabine resistance in PDAC via regulating PDIA3-DKC1-hENT in a stress granules-dependent manner. Acta Pharmacol Sin 46, 474–488 (2025). https://doi.org/10.1038/s41401-024-01387-5

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