SP25 Phospholipids

SP25 Overcoming persistence mechanisms of anti-tumoral agents by modulating the membrane phospholipid composition

Project leader: Andreas Koeberle

Background and previous work
Stress dramatically changes the cellular phospholipid composition, though the consequences on adaptive signalling responses are poorly understood. We found that phospholipids with polyunsaturated fatty acids (PUFA-PC) counteract Akt-signalling and identified p38 MAPK as missing link between stearoyl-CoA-desaturase 1 (which determines the ratio of monounsaturated fatty acids in phospholipids) and ER homeostasis. Ongoing studies suggest that PUFA-phosphatidylcholine sensitizes immortalized fibroblasts towards cytotoxic agents, including myxobacterial miurenamides which bind actin and potently suppress cancer cell proliferation.

Specific aims and working programme
We hypothesize that stress-induced changes in the cellular phospholipid composition i) regulate basal Akt and p38 MAPK activation, ii) affect ER-homeostasis and iii) thus modulate the susceptibility of cells towards the stressor. Our study aims to substantiate this hypothesis and explore possibilities for pharmacological intervention. Stress will be induced in NIH-3T3 fibroblasts by serum depletion, metabolic stressors (e.g., cyclohexamide), genotoxic agents (e.g., etoposide), disturbing ion homeostasis (e.g., by valinomycin), interference with mitogenic signalling (e.g., by staurosporine) and pro-inflammatory cytokines (e.g., tumor necrosis factor-α). We will investigate the effects on i) the phospholipid profile by UPLC-MS/MS, ii) initial stress signalling (i.e., PI3K, Akt, mTOR, p38 MAPK), iii) adaptive ER reactions (ER stress, UPR, ER-phagy) and iv) cell proliferation/survival in a time- and dose-dependent manner in NIH-3T3 fibroblasts. Selected stressors (i.e., miurenamides) will be encapsulated into liposomes consisting of PUFA-PC and evaluated for their anti-tumoral potential in cancer cell lines. We expect superior effects on mid- to long-term adaptive stress signalling (e.g., Akt, mTOR, GSK3, S6K, cyclins) and on cell proliferation/survival compared to the single components or liposomal formulations with saturated phospholipids.