The mechanism of phospholipid action

I. Membrane Distribution of Phospholipids and Polarity Establishment in Cell Migration

Cell migration relies on polarity differentiation between the leading edge and tail, with spatiotemporal phospholipid distribution playing a key role:

Phospholipid enrichment at the leading edge: The front membrane of migrating cells specifically enriches phosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂) and phosphatidylcholine (PC). PI(4,5)P₂ promotes actin polymerization by recruiting guanine nucleotide exchange factors (e.g., PIPKIγ) to drive pseudopod extension, while unsaturated fatty acid chains in PC (e.g., oleic acid) maintain membrane fluidity for easier front membrane deformation.

Phospholipid remodeling at the tail: The cell tail enriches phosphatidylserine (PS) and phosphatidylethanolamine (PE). The negative charge of PS binds to histones in the extracellular matrix to enhance tail adhesion, while the conical structure of PE induces negative membrane curvature, prompting tail contraction and detachment from the matrix. Experiments show that treating cancer cells with a PS 外翻 (externalization) inhibitor reduces migration speed by 40%.

II. Migration-Driving Mechanisms of Phospholipases and Lipid Signaling Molecules

1. Phospholipase A₂ (PLA₂) and Pseudopod Extension

PLA₂ hydrolyzes PC to generate lysophosphatidylcholine (LPC) and arachidonic acid (AA): The single-chain structure of LPC increases local membrane curvature to promote pseudopod protrusion, while AA activates cyclooxygenase (COX-2) as an inflammatory mediator to produce prostaglandin E₂ (PGE₂), enhancing front-end actin polymerization via the PI3K-AKT pathway. In breast cancer cells, a PLA₂ inhibitor decreases pseudopod formation rate by 60%.

2. Phospholipase C (PLC) and Migration Signal Cascades

PLC hydrolyzes PI(4,5)P₂ to generate diacylglycerol (DAG) and inositol trisphosphate (IP₃): DAG activates protein kinase C (PKC) to promote integrin-matrix adhesion, while IP₃ triggers endoplasmic reticulum Ca²⁺ release to activate calmodulin (CaM), driving myosin Ⅱ phosphorylation and cell body contraction. Fibroblasts with knocked-out PLCγ1 gene exhibit a 50% reduction in migration speed.

III. Spatiotemporal Signal Regulation by the Phosphatidylinositol (PI) Family

Phosphorylation modifications of PI form a dynamic signal network, precisely regulating migration stages:

Front-end localization of PI(3,4,5)P₃: Stimulated by growth factors (e.g., PDGF), PI3K converts PI(4,5)P₂ to PI(3,4,5)P₃, recruiting Akt and guanine nucleotide activating protein (GEF-H1) to the front membrane. Akt inhibits apoptosis, while GEF-H1 activates Rho family GTPases (e.g., Rac1) to promote lamellipodia formation. In lung cancer cells, a PI3K inhibitor reduces Rac1 activity by 70%, significantly weakening migration ability.

Rear-end regulation by PI(5)P: At the cell tail, inositol polyphosphate 5-phosphatase (SHIP) dephosphorylates PI(3,4,5)P₃ to PI(3,4)P₂, which is converted to PI(5)P by inositol monophosphatase. PI(5)P binds to contractile proteins (e.g., myosin light chain MLC) to promote tail focal adhesion disassembly, enabling cell detachment from the matrix. Macrophages lacking SHIP exhibit tail retention, with migration efficiency decreasing by 30%.

IV. Phospholipids and Integrin-Mediated Focal Adhesion Dynamics

Cell migration depends on the periodic assembly and disassembly of focal adhesions (FAs), with phospholipids acting as a bridge:

Phospholipid regulation during FA assembly: After integrin binds to the matrix, it activates focal adhesion kinase (FAK), which phosphorylates PI(4,5)P₂-binding proteins (e.g., Talin), promoting PI(4,5)P₂ enrichment at FA sites. PI(4,5)P₂ recruits talin and paxillin via electrostatic interactions, enhancing the connection between integrin and actin. Interfering with PI(4,5)P₂ production reduces FA stability by 50%.

Role of phospholipase D (PLD) in FA disassembly: As cells move forward, PLD at the FA rear hydrolyzes PC to produce phosphatidic acid (PA). The negative charge of PA binds to serine/threonine kinases in FAs (e.g., Src), promoting FA protein phosphorylation and subsequent focal adhesion disassembly. Cancer cells with PLD overexpression exhibit a 2-fold higher FA turnover rate and enhanced migration ability.

V. Special Mechanisms of Phospholipids in Tumor Cell Invasion

1. Phospholipid Reprogramming during EMT

During epithelial-mesenchymal transition (EMT), cells downregulate the epithelial marker E-cadherin while remodeling phospholipid composition: Increased expression of phosphatidylcholine transferase (PCYT1A) promotes PC synthesis, enhancing membrane fluidity for cell deformation; decreased expression of phosphatidylserine synthase (PSS1) reduces PS externalization, lowering intercellular adhesion. Knocking out PCYT1A in a breast cancer cell EMT model decreases invasion ability by 60%.

2. Phospholipid Regulation in Vasculogenic Mimicry

Highly invasive tumor cells can mimic vascular endothelial cells to form lumen structures (vasculogenic mimicry), relying on the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Activated PI3K promotes PI(3,4,5)P₃ enrichment at cell-cell contact sites, recruiting tight junction proteins (e.g., Claudin-5), while regulating actin tension via the RhoA/ROCK pathway to maintain lumen morphology. Blocking PI3K reduces tumor vasculogenic mimicry formation rate by 80%.

VI. Therapeutic Strategies Targeting Phospholipid Metabolism

Clinical application of PLA₂ inhibitors: Marprolol (Marpin), a selective PLA₂ inhibitor, reduces arachidonic acid release in tumor cells and inhibits pseudopod formation. Phase Ⅱ clinical trials show that combining it with chemotherapy decreases tumor invasion depth by 35% in colorectal cancer patients with liver metastases.

PI3K/mTOR dual-target drugs: Everolimus combined with the PI3K inhibitor Buparlisib blocks PI(3,4,5)P₃ production and Akt activation, dual-inhibiting breast cancer cell migration. Animal experiments show this combination reduces lung metastasis foci by 70%.

Conclusion

Phospholipids construct a multi-dimensional regulatory network in cell migration and invasion through membrane physical property regulation, lipid signal cascades, and focal adhesion dynamic modulation. From a basic research perspective, the spatiotemporal distribution and modification changes of phospholipids are key to decoding cell movement mechanisms. From a translational medicine angle, targeting phospholipid metabolic pathways provides new ideas for inhibiting diseases like tumor metastasis and tissue fibrosis. Combining single-cell lipidomics with live-cell imaging technologies in the future will further reveal the transient regulatory mysteries of phospholipids in cell migration.