Suppression of PRKAR1A Expression Enhances Antiproliferative and Apoptotic Effects of Protein Kinase Inhibitors and Chemotherapeutic Drugs on Cholangiocarcinoma Cells

Abstract

Suppression of protein kinase A regulatory subunit 1 alpha (PRKAR1A) has been proven to inhibitcholangiocarcinoma (CCA) cell growth and enhance apoptosis. In the present study, we aimed to determinesynergistic and/or additive effects of chemotherapeutic agents, including protein kinase inhibitors (i.e. sorafenib,sunitinib, gefitinib, Met inhibitor) and conventional chemotherapeutic drugs (i.e. 5-fluorouracil, doxorubicin,paclitaxel, gemcitabine), in PRKARIA knockdown CCA cell lines. The results revealed that PRKAR1A suppressedCCA cell lines demonstrated enhanced sensistivity to some chemotherapeutic drugs when compared to controlcells. Moreover, PRKAR1A knockdown in combination with either sorafenib or 5-fluorouracil increased apoptoticeffects on CCA cell lines. Therefore, selective inhibition of PRKAR1A appears to enhance the growth inhibitoryeffects of chemotherapeutic drugs as well as induce apoptotic cell death. Our findings suggest that additionalsuppression of PRKAR1A expression may increase the efficacy of conventional CCA chemotherapeutic treatment.Clinical studies in CCA patients now need to be conducted.