LPCAT2-mediated lipid droplet production supports pancreatic cancer chemoresistance and cell motility

Lipid droplet (LD) accumulation is one of the features in various tumors, whereas the significance of LD accumulation in pancreatic cancer progression remains unclear under chemotherapeutic condition. Since chemoresistance towards gemcitabine (GEM) is an obstacle for clinical therapy of pancreatic cancer, we sought to investigate the contribution of LD accumulation to GEM resistance. Herein, triacsin C (an inhibitor of LD production) dampened the proliferation, migration, and invasion of pancreatic cancer cells. The inhibition of LD accumulation induced by triacsin C or silencing of perilipin 2 (a marker of LD) sensitized cells to GEM treatment. Next, 75 paraffin-embedded samples and 5 pairs of frozen samples from pancreatic cancer patients were obtained for the detection of lysophosphatidylcholine acyltransferase 2 (LPCAT2; a LD-located enzyme contributing phosphatidylcholine synthesis) expression. The results revealed that LPCAT2 was upregulated in pancreatic cancer tissues, and its expression was correlated with clinical parameters and the basal LD content of cancer cell lines. Loss of LPCAT2 repressed the LD accumulation, GEM resistance, and cell motility. The enhancement of chemotherapy sensitivity was further confirmed in a xenograft model of mice in vivo. The carcinogenesis role of LPCAT2 was at least partly mediated by the LD accumulation. Then, signal transducer and activator of transcription 5B (STAT5B) activated the transcription of LPCAT2. Both LPCAT2 downregulation and triacsin C reversed the STAT5B-induced potentiation of malignant phenotypes in pancreatic cancer cells. In conclusion, LPCAT2-mediated lipid droplet production supported pancreatic cancer chemoresistance and cell motility, which was triggered by STAT5B.