PLK1 inhibition enhances gemcitabine-induced apoptosis through PLK1-dependent ERK1/2-BIM and AKT1/NOXA signals in pancreatic cancer cells

Background and Objective :Polo-like kinase 1 (PLK1) is a critical regulator of many cell cycle events, which has been found to be associated with resistance to cytotoxic drugs. In the present study, we investigates whether PLK1 regulates the sensitivity of pancreatic cancer cells to Gemcitabine (GEM) and its mechanism. Methods :We detected the expression of PLK1 in pancreatic cancer tissues and cell lines and study the effects of PLK1 and Gem on the growth and apoptosis of GEM-resistant pancreatic cancer PANC-1 cells and GEM sensitive BxPC-3 cells; We further investigate the effects of ERK1/2, AKT1, and pro-apoptotic genes PUMA, Bim, and Noxa on the growth and apoptosis of the aforementioned cells; We finally investigated the effect of the inhibitor of PLK1, onvansertib, combined with GEM on the growth of PANC-1 subcutaneous transplant tumors in nude mice and explored its possible mechanism of action. Results :GEM activates ERK1/2 and AKT1, leading to inhibition of pro-apoptotic Bim and Noxa expression, which is associated with GEM acquired resistance; The endogenous ERK1/2 and AKT1 levels is associated with endogenous GEM resistance. GEM participates in the regulation of cell growth and apoptosis by modulating ERK1/2/Bim and AKT1/Noxa signaling. By using PLK1 siRNA to inhibit PLK1 expression, ERK1/2 and AKT1 phosphorylation were significantly reduced, accompanied by an increase in ERK1/2-dependent Bim and AKT1- dependent Noxa upregulation and cell apoptosis. Targeting PLK1 enhances cell sensitivity to GEM by upregulating ERK1/2-dependent Bim and AKT1-dependent Noxa. PLK1 re-expression reverses cell sensitivity to GEM by inhibiting ERK1/2-dependent Bim and AKT1-dependent Noxa. The combination of onvansertib and GEM showed significant tumor growth inhibition in vivo, accompanied by inhibition of ERK1/2 and AKT1, and increased expression of Bim and Noxa. Conclusions :PLK1 inhibitor sensitizes PDAC cells to GEM in vitro and in vivo through inhibition of ERK1/2 and AKT1 phosphorylation, results in the upregulation of ERK1/2-dependent Bim and AKT1 dependent Noxa, leading to cell apoptosis. Collectively, the study supports an immediate clinical trial by combining GEM and onvansertib in treatment of GEM resistant PDAC patients.