Fatty acid oxidation: An emerging facet of metabolic transformation in cancer

Abstract

Cancer cells undergo metabolic reprogramming such as enhanced aerobic glycolysis, mutations in the tricarboxylic acid cycle enzymes, and upregulation of de novo lipid synthesis and glutaminolysis. These alterations are pivotal to the development and maintenance of the malignant phenotype of cancer cells in unfavorable tumor microenvironment or metastatic sites. Although mitochondrial fatty acid β-oxidation (FAO) is a primary bioenergetic source, it has not been generally recognized as part of the metabolic landscape of cancer. The last few years, however, have seen a dramatic change in the view of cancer relevance of the FAO pathway. Many recent studies have provided significant evidence to support a "lipolytic phenotype" of cancer. FAO, like other well-defined metabolic pathways involved in cancer, is dysregulated in diverse human malignancies. Cancer cells rely on FAO for proliferation, survival, stemness, drug resistance, and metastatic progression. FAO is also reprogrammed in cancer-associated immune and other host cells, which may contribute to immune suppression and tumor-promoting microenvironment. This article reviews and puts into context our current understanding of multi-faceted roles of FAO in oncogenesis as well as anti-cancer therapeutic opportunities posed by the FAO pathway.

Keywords: ATP; Cancer; Fatty acid β-oxidation; Lipolytic phenotype; NADPH.

Fig. 1.. FAO basics.

Long chain fatty acids enter cells via fatty acid transport proteins and then shuttled into the mitochondrion by the carnitine shuttle system. In the mitochondrion, fatty acids undergo oxidative removal of successive 2-carbon unit in the form of acetyl-CoA. Acetyl-CoA will be oxidized to CO₂ through the TCA cycle. Both FAO and the TCA cycle produce reduced electron carriers (NADH/FADH2), which will pass electrons to ETC to yield ATP. Apart from bioenergetic production, the carbon and hydrogen sources of FAO-generated acetyl CoA can be exported out of the TCA cycle to the cytoplasm to engage in NADPH and dNTP production as detailed in the text.

Fig. 2.. FAO signaling pathways and multi-faceted roles in cancer.

Shown on the left are signaling pathways regulated by FAO in physiological conditions. FAO is implicated in multiple aspects of tumorigenesis including cancer cell growth, survival, CSC maintenance, drug resistance, and metastasis. In addition to abnormal activation in cancer cells, FAO and related lipid metabolic processes are also reprogrammed in tumor-associated immune cells, adipocytes and endothelial cells, which may contribute to immune suppression and tumor-promoting microenvironment.