Simulation Study of Breast Cancer Lipid Changes Affecting Membrane Oxygen Permeability: Effects of Chain Length and Cholesterol.

Tumor radiotherapy relies on intracellular oxygen (O) to generate reactive species that trigger cell death, yet hypoxia is common in cancers of the breast. De novo lipid synthesis in tumors supports cell proliferation but also may lead to unusually high levels of the 16:1 palmitoleoyl (Y) phospholipid tail, which is two carbons shorter than the 18:1 oleoyl (O) tail abundant in normal breast tissue. Here, we use atomic resolution molecular dynamics simulations to test two hypotheses: (1) the shorter, 16:1 Y, tail of the de novo lipid biosynthesis product 1-palmitoyl,2-palmitoleoyl-phosphatidylcholine (PYPC) promotes lower membrane permeability relative to the more common lipid 1-palmitoyl,2-oleoylphosphatidylcholine (POPC), by reducing oxygen solubility in the interleaflet region, and (2) cholesterol further lessens the permeability of PYPC by reducing overall O solubility and promoting PYPC tail order adjacent to the rigid cholesterol ring system. The simulations conducted here indicate that PYPC has a permeability of 14 ± 1 cm/s at 37 °C, comparable to 15.4 ± 0.4 cm/s for POPC. Inclusion of cholesterol in a 1:1 ratio with phospholipid intensifies the effect of chain length, giving permeabilities of 10.2 ± 0.2 cm/s for PYPC/cholesterol and 11.0 ± 0.6 cm/s for POPC/cholesterol. These findings indicate that PYPC may not substantially influence membrane-level oxygen flux and is unlikely to hinder breast tissue oxygenation.