Phospholipids and Cell proliferation

Phospholipids, as the fundamental components of cell membranes, serve not only as physical barriers for cellular structures but also act as key molecules regulating cell proliferation by participating in signal transduction, dynamic membrane remodeling, and energy metabolism. The mechanisms of their role in cell growth and division can be analyzed from the following dimensions:

I. Basic Correlation Between Phospholipid Structural Diversity and Cell Proliferation

1. Phospholipid Composition and Membrane Microdomain Functions

Cell membranes are primarily composed of phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylethanolamine (PE), etc. Differences in fatty acid chain saturation and polar head groups of various phospholipids determine membrane fluidity and the formation of microdomains (e.g., lipid rafts). For instance, cell membranes with high phosphatidylcholine content exhibit strong fluidity, facilitating membrane remodeling during cell division; the distribution of PS on the inner side (normal cells) versus externalization (apoptotic cells) serves as a marker of cell proliferation status.

Lipid Rafts: Microdomains rich in sphingomyelin (SM) and cholesterol act as anchoring sites for growth factor receptors (e.g., EGFR) and signaling molecules. When cells receive proliferation signals (e.g., epidermal growth factor EGF), lipid rafts recruit EGFR and activate downstream pathways, driving cells from the G1 to S phase.

2. Dynamic Equilibrium of Phospholipid Metabolism

During cell proliferation, phospholipid synthesis and degradation must be balanced. For example, before cells enter the S phase, the activity of phosphatidylcholine synthase (CCTα) is upregulated to promote phosphatidylcholine synthesis for membrane expansion; phospholipase D (PLD) degrades PC to generate phosphatidic acid (PA), which acts as a second messenger to activate the mTORC1 pathway, regulating protein synthesis and cell growth.

II. Regulatory Mechanisms of Phospholipid Signaling Molecules on the Cell Cycle

1. Signaling Network of PI-Series Phospholipids

Role of PI(4,5)P₂: Upon growth factor stimulation, phospholipase Cγ (PLCγ) hydrolyzes PI(4,5)P₂ to produce diacylglycerol (DAG) and inositol trisphosphate (IP₃). DAG activates protein kinase C (PKC), promoting the expression of proto-oncogenes like c-Fos and c-Jun to advance the cell cycle; IP₃ releases calcium from endoplasmic reticulum stores, and calcium (Ca²⁺) activates calmodulin-dependent protein kinases, facilitating the G1 to S phase transition.

Regulation of PI(3,4,5)P₃: Phosphatidylinositol 3-kinase (PI3K) phosphorylates PI (4,5) P₂ to generate PI (3,4,5) P₃, recruiting Akt (protein kinase B) to the cell membrane for activation. Akt relieve cell cycle inhibition by phosphorylating downstream targets (e.g., GSK-3β, p27) and inhibits apoptosis, providing conditions for DNA replication.

2. Proliferation Regulation by Phosphatidic Acid and Phosphatidylserine

Dual Role of Phosphatidic Acid: Besides being a degradation product of phosphatidylcholine, it regulates ribosomal biosynthesis via the mTORC1 pathway. When cellular nutrients are sufficient, phosphatidic acid binds to mTORC1 and promotes its association with Rheb (small G protein), activating S6K1 and 4E-BP1 to accelerate mRNA translation and drive cells into the division phase.

Membrane Localization Switch of PS: In normally proliferating cells, PS is mainly distributed on the inner side of the cell membrane, maintained by ATP-dependent flippases. Abnormal flippase activity (e.g., cellular stress) leads to PS externalization, activating apoptotic signals and inhibiting cell proliferation. Thus, the localization homeostasis of PS is crucial for balancing cell proliferation and death.

III. Association Between Phospholipid Metabolic Enzymes and Cell Proliferation

1. Proliferation-Promoting Effects of Phospholipid Synthases

CCTα (Cytidine Cytosine Transferase α): As the rate-limiting enzyme for phosphatidylcholine synthesis, CCTα is highly expressed in tumor cells. Its activation promotes membrane expansion by increasing phosphatidylcholine content, while the generated phosphatidic acid participates in mTORC1 activation. For example, knocking down CCTα in breast cancer cells causes G1 phase arrest, reducing the cell proliferation rate by 50%.

Enzymes Related to PI Synthesis: Deletion of phosphatidylinositol synthase (PIS) leads to insufficient production of PI(4,5)P₂ and PI(3,4,5)P₃, weakening the activity of the PI3K-Akt pathway and blocking hepatocyte proliferation, confirming the necessity of PI synthesis for cell growth.

2. Bidirectional Regulation by Phospholipid Hydrolases

Proliferation-Promoting Effect of PLD: PLD is overexpressed in various cancer cells (e.g., lung, colon), catalyzing phosphatidylcholine to form phosphatidic acid, which activates the Raf-MEK-ERK pathway, promotes cyclin D1 expression, and drives cells across the G1/S checkpoint.

Dual Role of Phospholipase A₂ (PLA₂): PLA₂ hydrolyzes phospholipids to release arachidonic acid (AA), which can generate prostaglandin E2 (PGE2) via the cyclooxygenase (COX) pathway to promote cell proliferation. However, excessive AA induces oxidative stress, activating the p53 pathway to inhibit the cell cycle, exhibiting dose-dependent regulation.

IV. Structural Remodeling Functions of Phospholipids During Cell Division

1. Dynamic Membrane Changes in Mitosis

Prophase to Metaphase: The unsaturated fatty acid chains of phosphatidylethanolamine (PE) increase membrane curvature, facilitating spindle microtubule anchoring to the cell membrane. Meanwhile, local enrichment of PI(4,5)P₂ at the division poles recruits actin-binding proteins for spindle positioning.

Anaphase to Telophase: Specific changes in phospholipid distribution occur at the cell cleavage furrow. PS and PI(4,5)P₂ recruit contractile ring proteins (e.g., myosin Ⅱ) to drive cytokinesis; membrane fusion-related phospholipids (e.g., PC) participate in daughter cell membrane closure after division. Insufficient PC synthesis leads to cytokinesis failure and multinucleated cells.

2. Support for Proliferation by Organelle Membrane Phospholipids

Synergy Between ER Phospholipid Synthesis and Mitochondrial Phospholipid Transport: PE synthesized in the endoplasmic reticulum (ER) is transported to mitochondria via mitochondria-associated membranes (MAM) to maintain mitochondrial membrane potential and provide energy (ATP) for cell division. Abnormal phospholipid transport at MAM impairs mitochondrial function, arresting cells in the G2/M phase.

V. Phospholipid Abnormalities and Dysregulated Cell Proliferation in Diseases

1. Phospholipid Metabolic Reprogramming in Tumor Cells

Cancer cells upregulate phospholipid synthases (e.g., ACLY, FASN) to increase saturated fatty acid supply, synthesizing more PC and SM to support rapid proliferation. For example, ACLY deletion in liver cancer cells reduces PC synthesis, decreases membrane fluidity, and blocks cell division.

Mutations in the PI3K-Akt pathway (e.g., PTEN deletion) lead to continuous accumulation of PI (3,4,5) P₃, overactivating Akt to 解除 cell cycle inhibition and promote unlimited tumor cell proliferation.

2. Proliferation Abnormalities in Metabolic Diseases

Obesity Models: Excess free fatty acids (FFA) disrupt phospholipid metabolism, causing phosphatidic acid accumulation in hepatocytes, activating the AMPK-mTOR pathway, inducing proliferative disorders, and promoting the progression of non-alcoholic fatty liver disease (NAFLD) to liver cancer.

Atherosclerosis: Oxidized phospholipids (e.g., ox-LDL) disrupt phospholipid membrane homeostasis in vascular endothelial cells, activate the NF-κB pathway, promote abnormal smooth muscle cell proliferation, and exacerbate plaque formation.

VI. Proliferation Regulation Strategies Targeting Phospholipid Metabolism

1. Directions for Drug Development

PLD Inhibitors: FIPI (1-butanol) inhibits PLD activity, reduces phosphatidic acid production, blocks the Raf-ERK pathway, and decreases tumor cell proliferation by 30% in pancreatic cancer models.

PI3K Subtype-Selective Inhibitors: Idelalisib (PI3Kδ inhibitor) specifically suppresses the proliferation of B-cell lymphoma cells by reducing PI(3,4,5)P₃ production and has been approved by the FDA for hematological tumor treatment.

2. Nutritional Intervention and Phospholipid Supplementation

Supplementation with phosphatidylcholine-rich phospholipids (e.g., soybean lecithin) improves hepatic phospholipid metabolism and promotes normal liver regeneration.

DHA (docosahexaenoic acid), as a PUFA, can be incorporated into phospholipids to regulate membrane fluidity, inhibiting the migration and proliferation of breast cancer cells in vitro.

Conclusion

Phospholipids deeply participate in all aspects of cell proliferation through their triple roles of "structural support-signal transduction-energy metabolism". From signal activation in cell membrane microdomains, to cell cycle regulation driven by phospholipid metabolic enzymes, to membrane structural remodeling during division, their dynamic equilibrium forms the basis of normal cell growth. Abnormal phospholipid metabolism is closely associated with dysregulated cell proliferation in tumors and metabolic diseases, making targeting phospholipid metabolic pathways a new focus for disease intervention. Future research could focus on the application of phospholipid nanocarriers in proliferation-regulating drug delivery and the dynamic correlation between phospholipid distribution and the cell cycle at the single-cell level, providing a theoretical basis for precise regulation of cell growth.