Glutamine-Mediated Tumor Stromal Interaction: A Novel Target for Pancreatic Cancer Treatment
Abstract
Pancreatic ductal adenocarcinoma is a devastating disease with appallingly poor outcome. Conventional therapeutic approaches including gemcitabine-based combination chemotherapy offer modest survival benefit at the cost of increased toxicity. We have previously demonstrated that pancreatic stellate cells (PSCs) secrete glutamine (Q) to promote the growth of pancreatic cancer cells (PCCs), which can be attenuated by a natural compound palmatine (PMT). However, the precise mechanisms associated with Q- and PMT- mediated biological outcome have not been fully understood. Here, we demonstrated that PMT inhibits Q-stimulated STAT3 phosphorylation at both tyrosine 705 and serine 727, its downstream target surviving, and Q-stimulated increased proliferation, clonogenicity, anchorage independent growth, migration and invasion. Furthermore, RNA-seq analysis revealed that gene expression profile of PMT treatment under Q stimulation condition mimics STAT3 knockdown. These data suggest that PMT abrogates glutamine-induced biological outcome in part through STAT3. Given that both STAT3 and survivin are involved in therapeutic resistance of GEM and Abraxane (Abr), we tested the combination of PMT with GEM and Abr and found that PMT potentiates anti-proliferative effect of GEM and Abr in PSCs and PCCs and identified potential feedback activation mechanism that resist to PMT and GEM treatment. Taken together, this study demonstrated the potential clinical utility of PMT in the management of pancreatic cancer through inhibition of STAT3.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2021
- Accession Number
- AD1154907
Entities
People
- Xiaoyu Yang
Organizations
- University of Texas Health Science Center at San Antonio