Inhibition of STAT-3 sensitizes pancreatic cancer cells to chemoradiotherapy

Introduction Chemoradiotherapy (CRT) represents a putative treatment strategy for borderline resectable or unresectable pancreatic cancer, which may allow subsequent surgical resection in selected patients. However, a considerable percentage of tumors develop strategies to overcome radiation-induced cell killing. It is therefore important to unveil the underlying molecular mechanisms of this resistance. Activation of STAT3 represents a central event in inflammation-induced pancreatic carcinogenesis. Because we previously demonstrated that inhibition of STAT3 re-induced sensitivity of rectal cancer cells to CRT both in vitro and in vivo, we now explored inhibition of STAT3 signaling in pancreatic cancer cell lines.

Methods STAT3 expression and STAT3 phosphorylation (pSTAT3^Tyr705) was determined in pancreatic adenocarcinoma cell lines BxPC-3, Capan-1, Capan-2, L3.6, MIA PaCa-2, PANC-1, PaTu8988t using Western blot analysis. STAT3 reporter activity was determined by a dual luciferase reporter assay. Inhibition of STAT3 was employed using RNAi and the small molecule inhibitor Napabucasin, and sensitivity to CRT was assessed using colony formation assays.

Results While STAT3 was constitutively active in L3.6, MIA PaCa-2, Panc-1, and PaTu8988t cells, only BxPC-3, MIA PaCa-2, L3.6, and PaTu8988t cells show significant STAT3-dependent transcriptional reporter activity. Interestingly, we observed a positive correlation between STAT3 signaling activity and increasing resistance to CRT. Importantly, abrogation of STAT3 signaling using an siRNA resulted in treatment sensitization of cell lines with high STAT3 activity (BxPC-3, L3.6, MIA PaCa-2), while there was no effect in cells with STAT3 insensitivity (PANC-1), and in non-tumorigenic control cells (RPE-1). Furthermore, inhibition of STAT3 using Napabucasin likewise increased sensitivity to CRT in BXPC-3, but not PANC-1.

Conclusion These preliminary results suggest that STAT3 signaling may play a role in mediating resistance to CRT in pancreatic cancer. Inhibition of STAT3 may represent a putative treatment strategy to increase sensitivity to CRT in tumors with high STAT3 activity.

Publication History

Article published online:
07 September 2021