Triptolide exhibits dual anti-tumor effects through inhibiting autophagy and extracellular matrix activation in pancreatic cancer

Aim:The tumor microenvironment in pancreatic cancer, characterized by abundant desmoplastic stroma, has been implicated in the failure of chemotherapy. Therefore, developing therapeutic strategies targeting tumor and stromal cells is essential. Triptolide, a natural compound derived from the plant Tripterygium wilfordii, has shown antitumor activity in various cancers, including pancreatic cancer. However, its effects on pancreatic cancer cells and the microenvironment remain unclear. This study aimed to explore the effect of triptolide on tumor cells and the tumor microenvironment in pancreatic cancer.Methods:Cell Counting Kit-8, colony formation, apoptosis, and cell cycle assays were performed to determine the effect of triptolide on tumor cells. Additionally, co-culture assays were performed to explore the effects of the compound on cancer-associated fibroblasts (CAFs) in vitro. Orthotopic xenograft and subcutaneous tumor models were used to explore the antitumor and antistromal activation effects of triptolide in vivo. RNA sequencing was performed to identify the pathways involved in these processes in pancreatic cancer cells.Results:Triptolide inhibited the proliferation of pancreatic cancer cells and attenuated stromal activation in vitro and in vivo. Furthermore, it suppressed autophagy and induced apoptosis in pancreatic cancer cells by inhibiting the secretion of CXCL1. Extracellular matrix formation in CAFs was disrupted by suppressing the paracrine secretion of TGF-beta from tumor cells.Conclusion:These findings indicate that triptolide plays a dual antitumor role against tumor cells and CAFs, thus providing new insights into treating pancreatic cancer in the future.