Magtanong et al have demonstrated that MUFAs induce a
Magtanong et al. (2019) have demonstrated that MUFAs induce a ferroptosis-resistant state in cells in an ACSL3 (acyl-CoA synthetase long-chain family member 3) dependent manner. They observed that MUFAs did not increase the expression of GPX4, which opposes ferroptosis. However, they blocked plasma membrane lipid reactive oxygen species (ROS) accumulation and reduced PUFA incorporation into phospholipids. Specifically, ACSL3 is required for inducing the ferroptosis-resistant state and inhibiting saturated fatty Budesonide (SFA)-induced lipotoxicity. Their work suggests that exogenous MUFAs may alter cell membrane properties by displacing PUFAs such as AA, EPA, and DHA. It is possible that such displaced PUFAs, especially AA, are sequestered in the lipid droplets of the cytoplasm to prevent its tumoricidal action. However, it was previously shown that PUFAs are tumoricidal by enhancing free radical generation and accumulation of toxic lipid peroxides. Both iron and copper salts enhanced the cytotoxic action of PUFAs, implying that ferroptosis is at work (Das, 2011). How can these diametrically opposite actions of MUFAs and PUFAs be explained and what are their therapeutic implications? Fatty acids are essential nutrients (either obtained externally or derived by de novo synthesis and breakdown of cellular triacylglycerol (TAG) and phospholipid) that serve as building blocks of the body and participate in energy metabolism and cellular signaling pathways. Dysregulated fatty acid metabolism can result in metabolic disorders and carcinogenesis. Fatty acids can be processed by mitochondrial β-oxidation into acetyl-CoA that enters the tricarboxylic acid cycle to aid ATP generation or may get incorporated into TAG, phospholipids, or cholesterol esters. These two pathways need a common initial step of fatty acid activation by acyl-CoA synthetase (ACS) (Tang et al., 2018). Of the five isoforms of ACSLs (that have specific yet overlapping roles in the activation of PUFAs), ACSL3 and ACSL4 activate PUFAs. While ACSL3 prefers oleic acid (OA), ACSL4 favors AA and adrenic acid (AdA). ACSLs induce resistance to fatty acid-induced lipotoxicity and cell death in cancer cells. However, ACSL4 enables cells to undergo ferroptosis through oxidized AA and AdA. It is likely that ACSL4 directs AA metabolism via two different routes: (1) cell survival by enhancing the formation of eicosanoids such as prostaglandin E2 (PGE2), and (2) ferroptosis, by allowing AA to undergo peroxidation (see Figure 1). Since oxidized AA and AdA induce ferroptosis whereas ACSLs generally prevent lipotoxicity and cell death, it is likely that there is a threshold concentration that differentiates between survival and ferroptosis (Tang et al., 2018). At a lower concentration, such as the low levels found in tumor cells, AA is directed to the COX-2 pathway (which is activated in tumor cells) to promote survival. Higher or excess AA may produce Fenton reaction-induced oxidative stress that inhibits COX-2 (or minimizes the activity of COX-2) but activates the lipoxygenase (LOX) pathway (Kagan et al., 2017). This results in a decrease in PGE2 and enhances anti-inflammatory lipoxin A4 (LXA4) production. LXA4 inhibits tumor cell proliferation without interfering with the tumoricidal action of chemotherapeutic drugs and protects normal cells from the cytotoxic action of toxins (Polavarapu et al., 2018). These data raise the interesting possibility that normal and tumor cells have evolved distinctly different but mutually beneficial ways of regulating AA metabolism (Das, 2011). Normal cells metabolize AA to form adequate amounts of LXA4 to prevent inflammation, decrease PGE2 synthesis, and suppress toxic lipid peroxide accumulation to survive. In contrast, tumor cells contain decreased amounts of AA (and possibly higher amounts of MUFAs) and possess activated COX-2 to generate excess PGE2 that has pro-inflammatory and immunosuppressive action to facilitate tumor cell survival, proliferation, and metastasis. When excess AA is supplemented to tumor cells, toxic lipid peroxides accumulate and induce apoptosis and ferroptosis (Das, 2011; Figure 1). This proposal explains the controversial role of antioxidant vitamin E in cancer but agrees with the way AA (and other PUFAs) are handled by normal and tumor cells. Vitamin E in healthy cells prevents the peroxidation of AA and facilitates the formation of LXA4 that has cytoprotective actions and thus prevents carcinogenesis (Polavarapu et al., 2018). In contrast, vitamin E and GPX4 prevent peroxidation of AA, which encourages tumor cell growth. These results are intriguing in the light of the recent observation that ferroptic cancer cell death depends on lipid peroxidation by LOX enzymes and GPX4 (Tang et al., 2018., Hangauer et al., 2017). However, how exactly this shift in the synthesis of PGE2 and LXA4 in normal and tumor cells from AA occurs is not clear. The Solute carrier (SLC) family of membrane transport proteins, glycolysis, lactate, ACSL4, and HIF-1α (hypoxia inducible factor-1α) may play a role in modulating the expressions of COX-2 and LOX enzymes that consequently alter the balance between PGE2/LXA4 in normal and tumor cells and modulate ferroptosis and efferocytosis (Chen et al., 2010, Morioka et al., 2018).