2. Academic Validation
  3. STAT3 inhibition enhances gemcitabine sensitivity in pancreatic cancer by suppressing EMT, immune escape and inducing oxidative stress damage

STAT3 inhibition enhances gemcitabine sensitivity in pancreatic cancer by suppressing EMT, immune escape and inducing oxidative stress damage

  • Int Immunopharmacol. 2023 Jul 27;123:110709. doi: 10.1016/j.intimp.2023.110709.
Hangcheng Guo 1,  Zujian Hu 2,  Xuejia Yang 2,  Ziwei Yuan 2,  Yuanyuan Gao 2,  Jiawei Chen 2,  Lili Xie 2,  Chaoyue Chen 2,  Yangyang Guo 3,  Yongheng Bai 4
Affiliations

Affiliations

  • 1 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; The 404th Hospital of Mianyang, 621000 Sichuan, China.
  • 2 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
  • 3 Department of Thyroid and Breast Surgery, Ningbo First Hospital, Ningbo 315000, China.
  • 4 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: wzbyh@wmu.edu.cn.
PMID: 37515849 DOI: 10.1016/j.intimp.2023.110709
Abstract

Pancreatic Cancer (PC) is a highly-malignant tumor of the digestive system with a very poor prognosis and high mortality. Chemotherapy and PD-1/PD-L1 immune checkpoint blockade are important treatment strategies for advanced PC. However, chemotherapy resistance and poor therapeutic effect of immune checkpoint inhibitors is are the main clinical problems to be solved urgently at present. The effects of combined application of gemcitabine and STAT3 inhibition on the proliferation, Apoptosis, migration, and invasion of PC cells (PCCs) were investigated. In addition, oxidative stress (OS), Ferroptosis, immune escape, and the epithelial-mesenchymal transition (EMT) were evaluated. STAT3 inhibition with Stattic enhanced the inhibitory activity of gemcitabine on PCC proliferation by regulating the cell cycle. STAT3 inhibition enhanced mitochondrial-dependent Apoptosis in gemcitabine-treated PCCs, but did not induce Autophagy and Ferroptosis. Further study showed that the anti-proliferative and pro-apoptotic effects may be associated with increased OS damage by inactivating Nrf2-HO-1 signaling, as well as DNA damage by inducing the imbalance between ATM andATR-Chk1 pathway. In addition, STAT3 inhibition strengthened gemcitabine-mediated suppression in PCC invasion and migration by antagonizing SMAD2/3-dependent EMT. Moreover, the anti-tumorimmuneresponse of gemcitabine was upregulated by Stattic through reducing the expression of PD-L1 and CD47. Mechanistically, combined application of gemcitabine and Stattic suppressed the phosphorylation and nuclear expression of STAT3. Interestingly, the activities of Akt and β-catenin signaling were also regulated, suggesting that drug combination has a broad-spectrum signal regulation effect. STAT3 inhibition enhanced the sensitivity of PCCs to the chemotherapy drug gemcitabine by suppressing EMT and immune escape and inducing OS damage.

Keywords

EMT; Gemcitabine; PD-L1; Pancreatic cancer; STAT3.

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