De novo lipogenesis at the mitotic exit is used for nuclear envelope reassembly/expansion. Implications for combined chemotherapy

Abstract

Mitosis has been traditionally considered a metabolically inactive phase. We have previously shown, however, that extensive alterations in lipids occur as the cells traverse mitosis, including increased de novo fatty acid (FA) and phosphatidylcholine (PtdCho) synthesis and decreased lysophospholipid content. Given the diverse structural and functional properties of these lipids, we sought to study their metabolic fate and their importance for cell cycle completion. Here we show that FA and PtdCho synthesized at the mitotic exit are destined to the nuclear envelope. Importantly, FA and PtdCho synthesis, but not the decrease in lysophospholipid content, are necessary for cell cycle completion beyond G 2 /M. Moreover, the presence of alternative pathways for PtdCho synthesis renders the cells less sensitive to its inhibition than to the impairment of FA synthesis. FA synthesis, thus, represents a cell cycle-related metabolic vulnerability that could be exploited for combined chemotherapy. We explored the combination of fatty acid synthase (FASN) inhibition with agents that act at different phases of the cell cycle. Our results show that the effect of FASN inhibition may be enhanced under some drug combinations.

Fatty Acid Synthase: An Emerging Target in Cancer

“…Furthermore, exogenous palmitate fails to reverse the inhibitory effect, suggesting that endogenously synthesized FAs are critical for completion of the cell cycle [ 104 ]. In a follow-up study, upregulation of endogenous FA synthesis is shown to be directed towards the nuclear envelope at the mitotic exit [ 105 ]. Nuclear localization of FASN was first reported in 2014 where it was shown to correlate with disease aggressiveness in prostate cancer [ 67 ].…”

A fast-acting lipid checkpoint in G1 prevents mitotic defects

“…Indeed, live cell analysis confirms that reduced free fatty acid levels in G2 and mitosis can cause mitotic defects. Fatty acids that are synthesized late in the cell cycle are important for nuclear envelope formation 84 , possibly explaining why FASN inhibition in G2 can lead to mitotic defects. In this way, cells sense if there is insufficient lipid biosynthesis and halt the cell cycle by employing an anticipatory G1 lipid checkpoint that prevents the start of a typically over 12 hour-long process that would end in a defective mitosis when lipid composition is most critical.…”

Epigallocatechin gallate triggers apoptosis by suppressing de novo lipogenesis in colorectal carcinoma cells

“…Several agents that target specific metabolic pathways, including fatty acid synthesis, have been shown to have the therapeutic potential to improve cancer treatment efficacy. A reduction of key enzymes in the DNL pathway has been shown to cause a reduction in fatty acid products [27] and fatty acid oxidation (FAO) [12], resulting in a decrease in the proliferative, metastatic and invasive ability of cancer cells [67–76]. The mechanism of the anticancer effect of EGCG has been demonstrated to be mediated via inhibiting the fatty acid biosynthesis pathway [50,77–80].…”