Lipid metabolic reprogramming in cancer cells

Abstract

Many human diseases, including metabolic, immune and central nervous system disorders, as well as cancer, are the consequence of an alteration in lipid metabolic enzymes and their pathways. This illustrates the fundamental role played by lipids in maintaining membrane homeostasis and normal function in healthy cells. We reviewed the major lipid dysfunctions occurring during tumor development, as determined using systems biology approaches. In it, we provide detailed insight into the essential roles exerted by specific lipids in mediating intracellular oncogenic signaling, endoplasmic reticulum stress and bidirectional crosstalk between cells of the tumor microenvironment and cancer cells. Finally, we summarize the advances in ongoing research aimed at exploiting the dependency of cancer cells on lipids to abolish tumor progression.

Addressing metabolic heterogeneity in clear cell renal cell carcinoma with quantitative Dixon MRI

“…We also observed a significant negative correlation between FF and PE, another recently reported key lipidomic feature of ccRCC associated with tumor growth and proliferation (32). It is important to emphasize that MRI signal is derived from the mobile intracellular lipids (predominantly TG), not from the lipids in the membranes, which are essentially invisible to the Dixon MRI technique.…”

“…Hence, Dixon-MRI can be applied to noninvasively predict the abundance and alterations directly in intracellular lipids and indirectly in membrane-bound lipids, which are both linked to ccRCC tumor progression. It has been reported that cancer cells selectively activate cholesterol synthesis pathways to keep up with energy demand and for survival (32,33), and increased activity of lipogenic enzymes such as FASN is a known phenotype in ccRCCs (7,9). Additionally, FASN expression predicts poor prognosis in cancer patients in general (34), and specifically in ccRCC patients (7).…”

Untitled

“…In line with these data, abundant evidence shows that many tumors grow in the vicinity of adipocytes or metastasize to adipocyterich environments which act as an important reservoir of triglycerides [33]. The hydrolysis of these triglycerides produces free fatty acids used as an energy source by adjacent cancer cells [34,35]. The oxidation of these fatty acids becomes a crucial mechanism on which cancer cells depend to survive in nutrient-and oxygen-depleted environmental conditions [36] such as the hypoxic BMmicroenvironment, suggesting potential for therapeutic strategies aimed to exploit the lipid-related metabolic dependence.…”

Repurposing itraconazole as an anticancer agent

“…Since then, such changes in the lipid composition of cancer cells have been studied in association with drug resistance. In the 1970s, anti-fungal drugs were revealed to exert synergistic effects with certain chemotherapeutic drugs via altering the membrane lipid composition of cancer cells (22,23), and therapeutic strategies that target lipogenic enzymes have been investigated in preclinical and clinical studies (24). Aberrant activation of AKT is correlated with an increase in lipid raft formation, while the disruption of lipid rafts inhibits AKT activation (25).…”