Background
Pancreatic cancer cells are highly resistant to drug therapy; however, underlying causes remain largely unknown. We hypothesised that the activation of CXCL12-CXCR4 signalling confers drug resistance to pancreatic cancer cells by potentiating survival. CXCR4 is overexpressed in precancerous/malignant pancreatic lesions and cancer stem cells, and implicated in its pathogenesis.
Conclusion
Our findings demonstrate, for the first time, a role of CXCL12-CXCR4 signalling axis in conferring drug resistance to pancreatic cancer cells and suggest that it could serve as a novel therapeutic target for pancreatic cancer therapy, alone and in combination with the cytotoxic drug.
Methods
Effect of CXCR4 activation by CXCL12 on restricting the gemcitabine-induced cytotoxicity and stimulating the survival signalling was examined in pancreatic cancer cells by MTT, DNA laddering, caspase activity, immunoblot, and promoter-reporter assays. Subsequently, we examined the effect of CXCR4 antagonist, AMD3100, in abrogating the rescue effect of activated CXCL12-CXCR4 signalling.
Results
The pancreatic cancer cells treated with gemcitabine exhibited reduced cytotoxicity in the presence of CXCL12 as compared with the cells treated with drug alone. CXCL12 induced the activation of FAK, ERK, and Akt signalling pathways, enhanced transcriptional activities of β-catenin and NF-κB, and expression of survival proteins. AMD3100 arrested the CXCL12-induced pancreatic cancer cell growth and drug resistance.