Platelet-activating factor and metastasis: calcium-independent phospholipase A₂β deficiency protects against breast cancer metastasis to the lung

Abstract

We determined the contribution of calcium-independent phospholipase A(2)β (iPLA(2)β) to lung metastasis development following breast cancer injection into wild-type (WT) and iPLA(2)β-knockout (iPLA(2)β-KO) mice. WT and iPLA(2)β-KO mice were injected in the mammary pad with 200,000 E0771 breast cancer cells. There was no difference in primary tumor size between WT and iPLA(2)β-KO mice at 27 days postinjection. However, we observed an 11-fold greater number of breast cancer cells in the lungs of WT mice compared with iPLA(2)β-KO animals (P < 0.05). Isolated WT lung endothelial cells demonstrated a significant increase in platelet-activating factor (PAF) production when stimulated with thrombin [1 IU/ml, 10 min, 4,330 ± 555 vs. 15,227 ± 1,043 disintegrations per minute (dpm), P < 0.01] or TNF-α (10 ng/ml, 2 h, 16,532 ± 538 dpm, P < 0.01). Adherence of E0771 cells to WT endothelial cells was increased by thrombin (4.8 ± 0.3% vs. 70.9 ± 6.3, P < 0.01) or TNF-α (60.5 ± 4.3, P < 0.01). These responses were blocked by pretreatment with the iPLA(2)β-selective inhibitor (S)-bromoenol lactone and absent in lung endothelial cells from iPLA(2)β-KO mice. These data indicate that endothelial cell iPLA(2)β is responsible for PAF production and adherence of E0771 cells and may play a role in cancer cell migration to distal locations.

PRDX6 promotes tumor development via the JAK2/STAT3 pathway in a urethane-induced lung tumor model

“…GPx inhibits cisplatin-induced apoptosis via the downregulation of Bcl2 in H460 human lung cancer cells [42]. iPLA2 also contributes to lung metastasis by stimulating plateletactivating factor production [43]. Recently, we also reported that GPx and iPLA2 activities were increased by PRDX6 in lung tumor tissues [19,32].…”

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

“…Nude mice bearing PRDX6-overexpressing lung cancer cells exhibited increases in tumor size and weight and increased expression of both GPx and iPLA 2 ␤ , and these outcomes were inhibited when a mutant PRDX6 was used, suggesting that PRDX6 promotes lung tumor growth via GPx and iPLA 2 ␤ . Occurrence of breast cancer is often accompanied by metastasis to the lung and injection of E0771 breast cancer cells in the mouse mammary pads resulted in an 11-fold higher number of breast cancer cells in WT lungs, relative to lungs from iPLA 2 ␤ -null mice ( 377 ). Further, production of thrombin-stimulated platelet-activating factor in lung endothelial cells was increased in the WT lungs and absent in the iPLA 2 ␤ -null mice.…”

Oncogenic effects of PAFR ligands produced in tumours upon chemotherapy and radiotherapy

“…PGE 2 is derived from the metabolism of membrane phospho lipids, through the action of phospholipase A 2 (PLA 2 ). Both Ca 2+ dependent PLA 2 (cPLA 2 ) and Ca 2+ independent PLA 2 (iPLA 2 ; also known as PLA2G6) 6 cleave phosphatidyl choline into arachidonic acid and lyso phosphatidylcholine (FIG. 1).…”