New dawn for cancer cell death: Emerging role of lipid metabolism

Abstract

Background: Resistance to cell death, a protective mechanism for removing damaged cells, is a "Hallmark of Cancer" that is essential for cancer progression. Increasing attention to cancer lipid metabolism has revealed a number of pathways that induce cancer cell death.

Scope of review: We summarize emerging concepts regarding lipid metabolic reprogramming in cancer that is mainly involved in lipid uptake and trafficking, de novo synthesis and esterification, fatty acid synthesis and oxidation, lipogenesis, and lipolysis. During carcinogenesis and progression, continuous metabolic adaptations are co-opted by cancer cells, to maximize their fitness to the ever-changing environmental. Lipid metabolism and the epigenetic modifying enzymes interact in a bidirectional manner which involves regulating cancer cell death. Moreover, lipids in the tumor microenvironment play unique roles beyond metabolic requirements that promote cancer progression. Finally, we posit potential therapeutic strategies targeting lipid metabolism to improve treatment efficacy and survival of cancer patient.

Major conclusions: The profound comprehension of past findings, current trends, and future research directions on resistance to cancer cell death will facilitate the development of novel therapeutic strategies targeting the lipid metabolism.

Keywords: Cancer; Cell death; Lipid metabolism; Therapeutic strategy.

Figure 1

The role of lipid metabolism reprogramming in cancer cell death. (A) Increased exogenous lipid uptake by CD36 and LDLR promote carcinogenesis. (B) A network regulates the four systems and the entire transportation process. The elevated expression of ABCA1, HDL/ApoA-1, SR-B1 and CAV-1 accelerate cholesterol efflux, which lead to cancer cell apoptosis. (C) The increment of cholesterol esterification regulated by ACAT1 induces apoptosis. (D) Glucose increases N-glycosylation of SCAP, activates SREBPs, ultimately inhibits apoptosis of cancer cells. The biosynthesis pathway converts acetyl-CoA into cholesterol through HMGCs and HMGCR, which are the key speed-limiting enzymes. (E) The upregulation of enzymes promotes fatty acid synthesis and oxidation, then induces ferroptosis. (F) PLA2 and LPCAT2 induce LDs formation, stimulates cancer cell survival, and prevents apoptosis.

Figure 2

Crosstalk between lipid metabolism, oncogenic signaling, and epigenetic modifications and their links to metabolic disorders and cancer. Lipid metabolism and the epigenome interact in a bidirectional fashion with genetic and molecular drivers that regulate cancer. An in-depth understanding of the interplay between molecular drivers, metabolic reprogramming, and epigenetic modifications in cancer will clarify their relationships and contribute to the development of effective cancer therapies. (A) Hypermethylation of CD36 leads to apoptosis in lung cancer cells. Increased expression of FADS2 and SCD1 caused by DNA methylation and histone modifications blocks ferroptosis. (B) EHMT2 activates H3K9me1 and H3K9me2, upregulates the transcription of SREBF2, and then triggers autophagy. (C) Deletion of SIRT6 increases promoter H3K9 acetylation levels, resulting in enhanced apoptosis sensitivity. NNMT improves SIRT1 stability while reducing FoxO1 acetylation, lowering the susceptibility of apoptosis. (D) CHK2 phosphorylates PLIN2/3 dissociates from LDs and is degraded by Hsc70-mediated autophagy. (E) The Akt-mTORC1-RPS6 pathway inhibits FASN ubiquitination by upregulating the USP2a de-ubiquitinase and suppresses ubiquitination of SREBP1 and SREBP2 by repressing GSK-3β, thereby promoting hepatocellular carcinoma survival. (F) Glycosylation stabilizes SCAP and decreases its interaction with Insig-1, promoting glioblastoma growth.

Figure 3

Exogenous lipids and lipid metabolism-related genes from the TME regulate cancer cell death. A complicated combination of cancer cells, immune cells, and stromal cells composes the TME. LD-acquired and stored unsaturated fatty acids assist cancer cells survival under hypoxia when de novo synthesis of unsaturated fatty acids is inhibited. Adipokines like FABP4 boost the expression of fatty acid transporters like CD36, making it easier for non-cancer cells to uptake fatty acids. Fatty acids promote tumor growth in immune cells attracted to the TME, such as TAM and T cells. Cancer cells enter the stromal compartment through the basement membrane, activating stromal cells such as CAFs and adipocytes and influencing lipid metabolism.