2. Academic Validation
  3. YBX1 as a therapeutic target to suppress the LRP1-β-catenin-RRM1 axis and overcome gemcitabine resistance in pancreatic cancer

YBX1 as a therapeutic target to suppress the LRP1-β-catenin-RRM1 axis and overcome gemcitabine resistance in pancreatic cancer

  • Cancer Lett. 2024 Oct 10:602:217197. doi: 10.1016/j.canlet.2024.217197.
Borui Li 1,  Faliang Xing 1,  Jingyi Wang 2,  Xiaohong Wang 3,  Chenjie Zhou 1,  Guixiong Fan 1,  Qifeng Zhuo 1,  Shunrong Ji 1,  Xianjun Yu 4,  Xiaowu Xu 5,  Yi Qin 6,  Zheng Li 7
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
  • 2 Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, St Lucia, QLD 4067, Australia.
  • 3 Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 4 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: yuxianjun@fudanpci.org.
  • 5 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: xuxiaowu@fudanpci.org.
  • 6 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: qinyi@fudanpci.org.
  • 7 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: lizheng@fudanpci.org.
PMID: 39216548 DOI: 10.1016/j.canlet.2024.217197
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is highly malignant and has a poor prognosis, without effective therapeutic targets in common gene mutations. Gemcitabine, a first-line chemotherapeutic for PDAC, confers <10 % 5-year survival rate because of drug resistance. Y-box binding protein 1 (YBX1), associated with multidrug-resistance gene activation, remains unelucidated in PDAC gemcitabine resistance. In vivo and in vitro, we verified YBX1's promotional effects, especially gemcitabine resistance, in pancreatic Cancer cells. YBX1-induced LRP1 transcription by binding to the LRP1 promoter region significantly altered the concentration and distribution of β-catenin in pancreatic Cancer cells. Through TCF3, β-catenin bound to the promoter region of RRM1, a key gene for gemcitabine resistance, that promotes RRM1 expression. Combination therapy with the YBX1 inhibitor SU056 and gemcitabine effectively reduced gemcitabine resistance in in vivo and in vitro experiments. High YBX1 expression promoted pathogenesis and gemcitabine resistance in pancreatic Cancer through the YBX1-LRP1-β-catenin-RRM1 axis. Combining YBX1 inhibitors with gemcitabine may provide a new direction for combination chemotherapy to overcome gemcitabine resistance, which frequently occurs during chemotherapy for pancreatic Cancer.

Keywords

Gemcitabine resistance; Pancreatic ductal adenocarcinoma; RRM1; Wnt/β-catenin; YBX1.

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