Inhibition of Akt by polyunsaturated phosphatidylcholine – A novel approach for anti-cancer therapy
Konstantin Löser (PhD fellow sponsored by the PRC) – University Jena, Germany
Liposomal drug carrier systems consisting of cationic phospholipids gain importance in cancer chemotherapy but their own anti-tumoral potential has not been sufficiently evaluated so far. We have recently shown that phosphatidylcholine containing polyunsaturated fatty acids (PUFA-PC) suppresses cell proliferation by inhibiting the signaling of Akt (protein kinase B), a key kinase for proliferation and tumor progression.1) To investigate whether the inhibition of Akt signaling through PUFA-PC exhibits anti-cancer properties, the intracellular proportion of specific PUFA-PC species shall be specifically increased and the effect on Akt signaling, cell cycle progression, cell proliferation, and apoptosis be evaluated for multiple human cancer cell lines. PUFA-PC will either be directly supplemented (as liposomal formulation) or their cellular proportion will be increased by targeting phospholipid remodeling. Dietary PUFA-rich phospholipids (e.g., soybean and marine phospholipids) will be studied in comparison to correlate their claimed health benefits with the proportion and bioactivity of individual PL species. Moreover, we will investigate whether the combination of PUFA-PC and anti-cancer drugs (encapsulated in PUFA-PC liposomes) has superior anti-tumoral effects. Focus will be placed on the anti-tumoral actinomycin D, resveratrol, and indirubin-3’-monoxime, which were recently identified by us in a lipidomic screen to reprogram cells towards accumulating PUFA-PC. We speculate that combining exogenous and endogenous supply of PUFA-PC has additive/synergistic effects on the inhibition of Akt signaling and thus cell proliferation. In fact, diverse epidermiological and (pre)clinical studies show a reduced risk of some cancers and/or a sensitization of tumors towards chemotherapy by dietary PUFA intake (as ω3-fatty acids, soybean PC, fish and/or krill oils), though the results are conflicting.
Taken together, our project aims to provide a mechanistic basis for the known benefits of PUFA-rich diets and for estimating the potential of polyunsaturated phospholipids as excipients or as active ingredients in cancer therapy.
Benefit for the community
Our project has a strong focus on basic research related to the physiology and pharmacology of phospholipids. We want to provide a solid mechanistic basis for the hypothesized anti-tumoral properties of PUFA-PC (and compounds that alter its cellular proportion). Our approach might pave the way for preclinical studies addressing the potential of PUFA-PC as cancer-preventive dietary supplement, pharmacological excipient or even active/activity-supporting ingredient of chemotherapeutics.
We prepared multilaminar phospholipids vesicles loaded with cytotoxic compounds and explored the potential of phosphatidylcholine-bound polyunsaturated fatty acids (PUFA-PC) in overcoming Akt-dependent tumor resistance. Our study shows that the cytotoxic activities of distinct cytoskeleton-targeting agents are potentiated through Akt-dependent and -independent mechanisms. The synergistic regulation encompasses two phases, is associated with changes in the phospholipid composition, and stable over a broad time- and concentration range. By subcellular fractionation of fibroblasts and subsequent lipidomic analysis, we found that the combination of PUFA-PC with distinct cytotoxic agents evokes effects in different subcellular compartments, including the perinuclear region and the endoplasmic reticulum as the major loci of phospholipid remodeling. Multimodal imaging techniques provided deeper insights into how the cytoskeleton is linked to lipid metabolism and mitogenic signaling on the subcellular scale. To explore the mechanisms behind the synergism, we investigated the expression of lipogenic enzymes because we recently found that inhibition of de novo fatty acid biosynthesis induces similar phospholipid profiles.2) We further investigated the trafficking of signaling endosomes and addressed the time-dependent phosphorylation of eight survival kinases and their substrates, thereby identifying additional mechanisms that contribute to the synergistic effect. Finally, we discovered distinct algae species in a lipidomic screen of 23 algae as rich source of PUFA-PC, which allows the evaluation of the promising tumor-sensitizing properties of PUFA-PC in pre-clinical studies in the future.
Arachidonoyl-phosphatidylcholine oscillates during the cell cycle and counteracts proliferation by suppressing Akt membrane binding
Proc. Natl. Acad. Sci. USA 110, 2546-2551
Targeting de novo lipogenesis as a novel approach in anti-cancer therapy
Br. J. Cancer 118, 43-51
Acetyl-CoA carboxylase 1 regulates endothelial cell migration by shifting the phospholipid composition
J. Lipid Res. 59, 298-311
Vitamin A regulates Akt signaling through the phospholipid fatty acid composition
FASEB J. 31, 4566-4577
Stearoyl-CoA desaturase-1 and adaptive stress signaling
Biochem. Biophys. Acta 1861, 1719-1726