2. Academic Validation
  3. Targeting of oncogenic AAA-ATPase TRIP13 reduces progression of pancreatic ductal adenocarcinoma

Targeting of oncogenic AAA-ATPase TRIP13 reduces progression of pancreatic ductal adenocarcinoma

  • Neoplasia. 2023 Nov 30:47:100951. doi: 10.1016/j.neo.2023.100951.
Farrukh Afaq 1,  Sumit Agarwal 1,  Prachi Bajpai 1,  Sameer Al Diffalha 2,  Hyung-Gyoon Kim 1,  Shajan Peter 3,  Moh'd Khushman 4,  Subhash C Chauhan 5,  Priyabrata Mukherjee 6,  Sooryanarayana Varambally 2,  Upender Manne 7
Affiliations

Affiliations

  • 1 Department of Pathology, University of Alabama at Birmingham, USA.
  • 2 Department of Pathology, University of Alabama at Birmingham, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, USA.
  • 3 Department of Medicine, Division of Gastroenterology, University of Alabama at Birmingham, USA.
  • 4 Department of Medicine, Division of Medical Oncology, Washington University in St. Louis, USA.
  • 5 Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, USA.
  • 6 Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
  • 7 Department of Pathology, University of Alabama at Birmingham, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, USA. Electronic address: upendermanne@uabmc.edu.
PMID: 38039923 DOI: 10.1016/j.neo.2023.100951
Abstract

Thyroid hormone receptor-interacting protein 13 (TRIP13) is involved in Cancer progression, but its role in pancreatic ductal adenocarcinoma (PDAC) is unknown. Thus, we assessed the expression, functional role, and mechanism of action of TRIP13 in PDAC. We further examined the efficacy of TRIP13 inhibitor, DCZ0415, alone or in combination with gemcitabine on malignant phenotypes, tumor progression, and immune response. We found that TRIP13 was overexpressed in human PDACs relative to corresponding normal pancreatic tissues. TRIP13 knockdown or treatment of PDAC cells with DCZ0415 reduced proliferation and colony formation, and induced G2/M cell cycle arrest and Apoptosis. Additionally, TRIP13 knockdown or targeting with DCZ0415 reduced the migration and invasion of PDAC cells by increasing E-cadherin and decreasing N-Cadherin and vimentin. Pharmacologic targeting or silencing of TRIP13 also resulted in reduce expression of FGFR4 and STAT3 phosphorylation, and downregulation of the Wnt/β-catenin pathway. In immunocompromised mouse models of PDAC, knockdown of TRIP13 or treatment with DCZ0415 reduced tumor growth and metastasis. In an immunocompetent syngeneic PDAC model, DCZ0415 treatment enhanced the immune response by lowering expression of PD1/PDL1, increasing granzyme B/perforin expression, and facilitating infiltration of CD3/CD4 T-cells. Further, DCZ0415 potentiated the anti-metastatic and anti-tumorigenic activities of gemcitabine by reducing proliferation and angiogenesis and by inducing Apoptosis and the immune response. These preclinical findings show that TRIP13 is involved in PDAC progression and targeting of TRIP13 augments the Anticancer effect of gemcitabine.

Keywords

Immune response; Metastasis; Pancreatic ductal adenocarcinoma; TRIP13; Tumor progression.

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