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

Abstract

Pancreatic cancer is currently one of the most lethal diseases. In recent years, increasing evidence has shown that reprogrammed metabolism may play a critical role in the carcinogenesis, progression, treatment and prognosis of pancreatic cancer. Affected by internal or external factors, pancreatic cancer cells adopt extensively distinct metabolic processes to meet their demand for growth. Rewired glucose, amino acid and lipid metabolism and metabolic crosstalk within the tumor microenvironment contribute to unlimited pancreatic tumor progression. In addition, the metabolic reprogramming involved in pancreatic cancer resistance is also closely related to chemotherapy, radiotherapy and immunotherapy, and results in a poor prognosis. Reflective of the key role of metabolism, the number of preclinical and clinical trials about metabolism-targeted therapies for pancreatic cancer is increasing. The poor prognosis of pancreatic cancer patients might be largely improved after employing therapies that regulate metabolism. Thus, investigations of metabolism not only benefit the understanding of carcinogenesis and cancer progression but also provide new insights for treatments against pancreatic cancer.

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

“…Under hypoxic conditions, the up-regulation of enzymes involved in fatty acid and cholesterol biosynthesis including citrate synthase, fatty acid synthase (FASN), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is observed in many cancer types including pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma [139][140][141]. A common single carbon source for both fatty acid and cholesterol biosynthesis is acetyl residue activated and carried by co-enzyme A, acetyl-CoA, which is supplied under physioxia condition by PDC.…”

Transcriptome sequencing analysis reveals unique and shared antitumor effects of three statins in pancreatic cancer

“…High-concentration statins (20 µM) can induce pancreatic cancer cell death in vitro , and this concentration may potentially be achieved by targeted implantation. We should therefore be cautious when statins are used clinically to treat cancer in future, particularly when it comes to the statin concentrations and the metabolic status of the cancer cells ( 46 , 47 ).…”

DNAJA1 dysregulates metabolism promoting an anti-apoptotic phenotype in pancreatic ductal adenocarcinoma

“…Poor survival outcomes and treatment challenges are driving forces to identify new PDAC targets in order to develop alternative therapies and resolve existing challenges in PDAC management (4). Metabolic dysregulation has been described as the basis of cancer pathology (5-7) with nearly all forms of PDAC characterized by aberrant aerobic glycolysis and glutaminolysis (8). Analyzing the regulatory roles of these pathways has presented promising nonchemotherapeutic PDAC treatment potential (8).…”

“…Metabolic dysregulation has been described as the basis of cancer pathology (5-7) with nearly all forms of PDAC characterized by aberrant aerobic glycolysis and glutaminolysis (8). Analyzing the regulatory roles of these pathways has presented promising nonchemotherapeutic PDAC treatment potential (8).…”

“…In these D1 cells, we observed significant dysregulation in fundamental metabolic pathways, marginal loss of mitochondrial dispersion, and loss of lysosomal integrity, which collectively impacted cellular survival. DNAJA1 overexpression exhibits a distinct impact on tumor specific metabolic processes like aerobic glycolysis and glutaminolysis, which is coupled with a response specific to the two phenotypically unique pancreatic cancer cells (8,19,20).…”