Abstract
Gemcitabine (GEM) resistance is a critical issue for pancreatic cancer treatment. The involvement of epigenetic modification in GEM resistance is still unclear. We established a GEM-resistant subline PANC-1-R from the parental PANC-1 pancreatic cancer cells and found the elevation of various chromatin-modifying enzymes including G9a in GEM-resistant cells. Ectopic expression of G9a in PANC-1 cells increased GEM resistance while inactivation of G9a in PANC-1-R cells reduced it. Challenge of PANC-1 cells with GEM increased the expression of stemness markers including CD133, nestin and Lgr5 and promoted sphere forming activity suggesting chemotherapy enriched cancer cells with stem-like properties. Inhibition of G9a in PANC-1-R cells reduced stemness and invasiveness and sensitized the cells to GEM. We revealed interleukin-8 (IL-8) is a downstream effector of G9a to increase GEM resistance. G9a-overexpressing PANC-1-R cells exhibited autocrine IL-8/CXCR1/2 stimulation to increase GEM resistance which could be decreased by anti-IL-8 antibody and G9a inhibitor. IL-8 released by cancer cells also activated pancreatic stellate cell (PSC) to increase GEM resistance. In orthotopic animal model, GEM could not suppress tumor growth of PANC-1-R cells and eventually promoted tumor metastasis. Combination with G9a inhibitor and GEM reduced tumor growth, metastasis, IL-8 expression and PSC activation in animals. Finally, we showed that overexpression of G9a correlated with poor survival and early recurrence in pancreatic cancer patients. Collectively, our results suggest G9a is a therapeutic target to override GEM resistance in the treatment of pancreatic cancer.
Highlights
Pancreatic cancer is one of the most lethal malignancies in the world
To identify novel proteins involving in GEM resistance, we investigated the changes of histone modifying enzymes by using PCR array
We profiled the expression of histone modifying enzymes by using array-based approach to elucidate the alterations of these enzymes in GEM-resistant pancreatic cancer cells
Summary
Pancreatic cancer is one of the most lethal malignancies in the world. The features of late diagnosis, highly metastatic ability and ineffective chemo- and radiotherapies lead to high mortality with a 5-year overall survival (OS) rate less than 5% [1]. GEM is an important chemotherapeutic drug for pancreatic cancer patients [4, 5]. The reasons for a low response rate could attribute to the intrinsic chemoresistance to GEM or the acquired resistance developed after repeated exposure. Nucleoside analogs like GEM are imported into cancer cells via specialized transporter systems including human equilibrative nucleosides transporters (hENTs) and concentrative nucleosides transporters and down-regulation of the transporters may increase drug resistance [7, 8]. Low expression of hENT1 in pancreatic cancer patients displays poor OS and diseasefree survival (DFS) [9]. Deficiency of deoxycytidine kinase is frequently found in pancreatic cancer cells and contributes to inherent or induced GEM resistance in a portion of patients [11]. Up-regulation of ribonucleotide reductase expression attenuates GEM cytotoxicity and provides another mechanism of GEM resistance [13]
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