Upregulation of pyruvate kinase M2 expression by fatty acid synthase contributes to gemcitabine resistance in pancreatic cancer

Abstract

Pancreatic cancer has one of the highest mortality rates of all cancer types. Fatty acid synthase (FASN) is a multifunctional protein homodimer that can convert acetyl coenzyme A (CoA) and malonyl-CoA into palmitate, thus regulating lipogenesis. FASN overexpression has also been shown to cause resistance to gemcitabine, a chemotherapy treatment for pancreatic cancer; however, the mechanism by which this happens is unclear. Analysis of gene expression of FASN and pyruvate kinase M2 (PKM2) in pancreatic cancer was performed using Oncomine microarray gene expression datasets, which demonstrated that FASN and PKM2 were upregulated in pancreatic cancer compared with normal tissue. Specifically, it was demonstrated that FASN enabled the upregulation of PKM2 expression at the mRNA and protein levels, increasing the glucose consumption rate in pancreatic cancer cells. The present study also revealed that decreased levels of FASN reduced resistance to gemcitabine treatment, which was induced by PKM2 overexpression in pancreatic ductal adenocarcinoma cells. Therefore, FASN may represent a novel therapeutic target in pancreatic cancer.

3F‑Box protein 32 degrades ataxia telangiectasia and Rad3‑related and regulates DNA damage response induced by gemcitabine in pancreatic cancer

“…Reverse transcription-quantitative polymerase chain reaction. Total RNA was extracted from PANC-1 cells using TRIzol ® reagent (Life Technologies, Thermo Fisher Scientific, Inc.), as previously described (11). The cDNA was synthesized using Superscript II reverse transcriptase (Thermo Fisher Scientific).…”

Metabolism of pancreatic cancer: paving the way to better anticancer strategies

“…In lipid metabolism, FASN expression is upregulated, which is also crucial for gemcitabine resistance. Overexpressed FASN in pancreatic cancer cells upregulates PKM2 expression, promoting glycolysis and gemcitabine resistance [159]. PKM2 also plays a nonmetabolic role in chemoresistance by inhibiting gemcitabine-induced TP53 signaling and subsequent apoptosis [160].…”

The role of pyruvate kinase M2 in anticancer therapeutic treatments (Review)

“…The resistance of pancreatic cancer cells to GEM involves PKM2 expression and its nonmetabolic function. Thus, PKM2 should be considered a therapeutic target in GEM-resistant pancreatic cancer cells (70,71). The role of PKM2 in GEM resistance is demonstrated in Fig.…”