Lipid metabolism in pancreatic cancer: emerging roles and potential targets

Abstract

Pancreatic cancer is one of the most serious health issues in developed and developing countries, with a 5-year overall survival rate currently <9%. Patients typically present with advanced disease due to vague symptoms or lack of screening for early cancer detection. Surgical resection represents the only chance for cure, but treatment options are limited for advanced diseases, such as distant metastatic or locally progressive tumors. Although adjuvant chemotherapy has improved long-term outcomes in advanced cancer patients, its response rate is low. So, exploring other new treatments is urgent. In recent years, increasing evidence has shown that lipid metabolism can support tumorigenesis and disease progression as well as treatment resistance through enhanced lipid synthesis, storage, and catabolism. Therefore, a better understanding of lipid metabolism networks may provide novel and promising strategies for early diagnosis, prognosis estimation, and targeted therapy for pancreatic cancer patients. In this review, we first enumerate and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in pancreatic cancer. In addition, we summarize preclinical studies and clinical trials with drugs targeting lipid metabolic systems in pancreatic cancer. Finally, we highlight the challenges and opportunities for targeting lipid metabolism pathways through precision therapies in pancreatic cancer.

Keywords: clinical trials; lipid metabolism; pancreatic cancer; targeting therapy.

FIGURE 1

Process of lipid uptake. Digestion of lipids in food mainly occurs in the small intestine, where they are absorbed into the blood. The exogenous uptake of FAs from the surrounding microenvironment is facilitated by specialized transporters, including CD36, FATPs, and FABPs. Cholesterol carried by LDL particles in the blood can be taken up by LDLR at the basal surface of cells. Abbreviations: CD36, fatty acid translocase; FATPs, fatty acid transport proteins; FABPs, fatty acid‐binding proteins. LDL, low‐density lipoprotein; LDLR, low‐density lipoprotein receptor

FIGURE 2

The source of acetyl‐CoA in cancer cells. Cancer cells obtain acetyl‐CoA from ACLY‐catalyzed citrate and ACSS‐catalyzed acetate, which is used for lipid synthesis. Additionally, glutamine and glucose can contribute to citrate production through the TCA cycle. Each solid blue arrow represents a specific biological process respectively in the figure. The dotted arrow means the process of transporting mediated by transporters. Dark triangles following the enzymes represent the alteration in cancer cells: upward means upregulation; downward means downregulation. Abbreviations: GLUT1, glucose transporter 1; MCT, monocarboxylate transporter; ASCT2, also named SLC1A5, solute carrier family 1 member 5; PDH, pyruvate dehydrogenase; GLS, glutaminase; IDH, isocitrate dehydrogenase; ACLY, ATP‐citrate lyase; ACSS, acyl‐CoA synthetase short‐chain family; TCA, tricarboxylic acid

FIGURE 3

The synthesis of FAs and cholesterol. FA and cholesterol biosynthesis both starts with acetyl‐CoA. Acetyl‐CoA is catalyzed into a series of unsaturated FAs by ACC, FSAN, and SCD in sequence. The production of cholesterol is mediated by several key enzymes, including ACAT, HMGCR, and SM. Furthermore, cholesterol can be converted to CE by SOAT, which is stored in LDs. The solid arrow represents a one‐step specific biological process, whereas the dotted arrow represents a multi‐step specific biological process. Red triangles following the enzymes represent the alteration in PC cells: upward means upregulation; downward means downregulation. Abbreviations: FAs, fatty acids; ACC, Acetyl‐CoA carboxylase; FASN, fatty acid synthase; SCD, stearoyl‐CoA desaturase; MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids; ACAT, Acetyl‐CoA acetyltransferase; HMGCR, 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A reductase; SM, Squalene monooxygenase; SOAT, Sterol‐o‐acyltransferase; CE, cholesterol ester; LDs, lipid droplets. CD36, fatty acid translocase; FATP, fatty acid transport protein; FABP, fatty acid‐binding protein. LDLR, low‐density lipoprotein receptor

FIGURE 4

The landscape of lipid metabolism in PC cells and its potential targets in PC treatment. Abbreviations: ACLY, ATP‐citrate lyase; ACSS, acyl‐CoA synthetase short‐chain family; FAs, fatty acids; ACC, Acetyl‐CoA carboxylase; FASN, fatty acid synthase; SCD, stearoyl‐CoA desaturase; MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids; ACAT, Acetyl‐CoA acetyltransferase; HMGCR, 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A reductase; SM, Squalene monooxygenase; SOAT, Sterol‐o‐acyltransferase; CE, cholesterol ester; LD, lipid droplet; LDL‐C, low‐density lipoprotein cholesterol; SREs, sterol regulatory elements; SREBP1/2, sterol regulatory element (SRE)‐binding protein 1/2; TCA, tricarboxylic acid; TAG, triacylglycerol; CPT1, carnitine palmitoyltransferase 1; EGCG, epigallocatechin gallate