Abstract

Abnormal lipid de novo lipogenesis and reprogramming of lipid metabolism have been associated with the development and progression of various cancers, including pancreatic cancer. Gemcitabine (GEM) combined with albumin-bound paclitaxel (nab-PTX) is the first-line chemotherapeutic agent for pancreatic cancer. There have been many studies on the molecular mechanisms of gemcitabine and paclitaxel in cancer treatment. Still, the effects of the combination on lipid metabolism and the specific mechanisms have not been explored. This study found that GEM combined with nab-PTX inhibited pancreatic cancer cell proliferation and de novo lipogenesis. The exact mechanism is that GEM combined with nab-PTX induces adenosine triphosphate (ATP) depletion and activates AMP-activated protein kinase (AMPK) in pancreatic cancer cells, which in turn inhibits sterol regulatory element-binding protein 1 (SREBP1) expression and nuclear translocation, and ultimately inhibits de novo lipogenesis in pancreatic cancer cells. In addition, we found that the novel lipid-lowering drug ETC-1002 significantly enhanced the inhibitory effect of GEM combined with nab-PTX on de novo lipogenesis in pancreatic cancer cells. These findings establish a link between GEM combined with nab-PTX and lipid metabolism, and the discovery of the novel lipid-lowering drug ETC-1002 provides a potential therapeutic strategy for pancreatic cancer.

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