Journal
FRONTIERS IN ONCOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2022.870473
Keywords
pancreatic cancer; ER stress; cell senescence; proteasome; autophagy
Categories
Funding
- NIH/NCATS
- University of Kansas Research Institute (Kansas, USA)
- Mosby Lincoln Foundation
- Donlan Foundation (Kansas, USA)
- University of Kansas Cancer Center support grant [P30 CA168524]
- GR's Foundation
Ask authors/readers for more resources
Compound C150 has been found to inhibit epithelial-to-mesenchymal transition in pancreatic cancer cells by inducing endoplasmic reticulum stress and increasing proteasome activity. It also induces G2/M cell cycle arrest, inhibits cell proliferation, and reduces tumor growth and ascites occurrence in a mouse model.
Pancreatic cancer is a devastating disease with a dismal prognosis and poor treatment outcomes. Searching for new agents for pancreatic cancer treatment is of great significance. We previously identified a novel activity of compound C150 to inhibit pancreatic cancer epithelial-to-mesenchymal transition (EMT). Here, we further revealed its mechanism of action. C150 induced ER stress in pancreatic cancer cells and subsequently increased proteasome activity by enhancing proteasome assembly, which subsequently enhanced the degradation of critical EMT transcription factors (EMT-TFs). In addition, as cellular responses to ER stress, autophagy was elevated, and general protein synthesis was inhibited in pancreatic cancer cells. Besides EMT inhibition, the C150-induced ER stress resulted in G2/M cell cycle arrest, which halted cell proliferation and led to cellular senescence. In an orthotopic syngeneic mouse model, an oral dose of C150 at 150 mg/kg 3x weekly significantly increased survival of mice bearing pancreatic tumors, and reduced tumor growth and ascites occurrence. These results suggested that compound C150 holds promises in comprehensively inhibiting pancreatic cancer progression.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available