Lithium and an EPAC-specific inhibitor ESI-09 synergistically suppress pancreatic cancer cell proliferation and survival

Xinshuo Wang, Cheng Luo, Xiaodong Cheng, and Meiling Lu

State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China, and Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA

Acta Biochim Biophys Sin 2017, 49: 573–580; doi: 10.1093/abbs/gmx045

Our previous studies showed that while lithium suppresses proliferation and induces apoptosis in pancreatic cancer cells, the inhibition of exchange proteins directly activated by cyclic adenosine monophosphate (cAMP) (EPAC)1 blocks pancreatic cancer cell migration and invasion. In this study, we further investigated the combinatory effects of lithium and EPAC-specific inhibitor (ESI)-09, an EPAC-specific inhibitor, on pancreatic cancer cell proliferation and viability, and explored whether lithium synergistically cooperates with EPAC inhibition in suppressing pancreatic cancer cell tumorigenicity. The cell viability of pancreatic cancer cell lines PANC-1 and MiaPaCa-2 was measured after 48 h of incubation with different dose combination of lithium and ESI-09. Flow cytometric analysis was carried out to further verify the impact of lithium and ESI-09 upon PANC-1 cell proliferation and apoptosis. To investigate the mechanism that the effects generated by lithium and ESI-09 on PANC-1 cells, the intracellular cAMP level was measured by an ELISA-based cAMP immunoassay. Our data showed that lithium and ESI-09 synergistically inhibit pancreatic cancer cell growth and survival. Furthermore, our results revealed a novel mechanism in which the synergism between lithium and ESI-09 is not mediated by the inhibitory effect of lithium toward GSK3β, but by lithium's ability to suppress cAMP/protein kinase A signaling.

Combination of LiCl and ESI-09 inhibited the cell proliferation of PANC-1 cells

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