Novel compound C150 inhibits pancreatic cancer through induction of ER stress and proteosome assembly.

Autor:	Wang T; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas, KS, United States., Chen P; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas, KS, United States., Weir S; Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS, United States., Baltezor M; Biotechnology Innovation and Optimization Center, University of Kansas, Lawrence, KS, United States., Schoenen FJ; Higuchi Biosciences Center, University of Kansas, Lawrence, KS, United States.; Medicinal Chemistry Core Laboratory, Lead Development and Optimization Shared Resource, University of Kansas Cancer Center, Lawrence, KS, United States., Chen Q; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas, KS, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2022 Oct 05; Vol. 12, pp. 870473. Date of Electronic Publication: 2022 Oct 05 (Print Publication: 2022).
DOI:	10.3389/fonc.2022.870473
Abstrakt:	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 3× 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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Wang, Chen, Weir, Baltezor, Schoenen and Chen.)
Databáze:	MEDLINE
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