Abstract
Simple SummaryCancer cells directly control nutrient uptake and utilization in a different manner from that of normal cells. These metabolic changes drive growth, proliferation of cancer cells as well as their ability to develop resistance to traditional therapies. We review published studies with pre-clinical models, showing the essential roles of lipid metabolism in anticancer drug resistance. We also discuss how changes in cellular lipid metabolism contribute to the acquisition of drug resistance and the new therapeutic opportunities to target lipid metabolism for treating drug resistant cancers.Metabolic reprogramming is crucial to respond to cancer cell requirements during tumor development. In the last decade, metabolic alterations have been shown to modulate cancer cells’ sensitivity to chemotherapeutic agents including conventional and targeted therapies. Recently, it became apparent that changes in lipid metabolism represent important mediators of resistance to anticancer agents. In this review, we highlight changes in lipid metabolism associated with therapy resistance, their significance and how dysregulated lipid metabolism could be exploited to overcome anticancer drug resistance.
Highlights
Many oncogenic mutations resulting in the aberrant activation of several signaling pathways can reprogram cancer cell metabolism to such an extent that metabolic reprogramming is considered one of the major hallmarks of cancer [1]
SCD1 inhibition is potentially responsible for adverse effects since the accumulation of SCD1 substrates result in inflammation, atherosclerosis, as well as liver and pancreatic dysfunction in pre-clinical models [104] (ii) The rationale for such a combination is based on the fact that lipid targeted drugs and standard treatment address two complementary aspects of the metabolism and that neither drug alone can succeed in promoting cell death
Lipid metabolism plays a central role in cancer resistance, via an increased availability of lipids conferred by adipocyte environment and through profound changes in cancer cell lipid metabolism
Summary
Many oncogenic mutations resulting in the aberrant activation of several signaling pathways can reprogram cancer cell metabolism to such an extent that metabolic reprogramming is considered one of the major hallmarks of cancer [1]. Apart from lipogenesis, it was observed that FAs, either from extracellular sources or mobilized from internal lipid stores, can be oxidized in cancer cell mitochondria (Figure 1B) Under these conditions, lipids are used as catalytic fuels, a process called fatty acid oxidation (FAO) or lipolysis, to provide energy for cancer cells via ATP production. Cancer cells uptake FAs released by adipocytes, which in turn are oxidized into mitochondria and provide the energetic needs for cancer cell proliferation, survival, invasion, metastasis and drug resistance [25,31,34,36,37] These results highlight the cross-talk between adipose tissue and cancer cells enhancing cancer FAO and aggressiveness. We discuss the potential of reversing chemoresistance via lipid metabolism regulation
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