Staff Members of the Institute of Biochemistry, TU - Institut für ...

polar acyl residues in position sn-2 of the glycerol backbone. The respective compounds
trigger an intracellular signaling network including sphingomyelinases, (MAP) kinases and
transcription factors thereby inducing proliferation or apoptosis of vascular cells. Both
phenomena largely depend on the specific action of sphingolipid mediators that are acutely
formed upon cell stimulation by the oxidized lipids. Fluorescence microscopic studies on
labeled lipid analogs revealed that the short-chain phosphatidylcholines are easily transferred
from the aqueous phase into the cell plasma membrane and eventually spread throughout the
cells. Under these circumstances, the biologically active compounds are very likely to
interfere directly with various signaling components inside the cells, which finally decide
about cell growth or death. Investigations are being performed on the levels of the
sphingolipidome, the enzyme activities responsible for ceramide homeostasis, the proteome
and the transcriptome to find the primary molecular targets and their downstream elements
that are the functional components of lipid-induced cell death.
Sphingomyelin
acid
Sphingomyelinase
Ceramide
JNK
p38 MAPK
Caspase 3
Oxidized -
O
Phospholipids
H
O
O
O
O
O
O
O P
O
O
OH
+
N
O
O
O
O
O P
O
OH
N +
O
ERK
AKT/PKB
NFkB
PROLIFERATION
SURVIVAL
OXPHOS-EuroMEMBRANE
1.2. Toxicity of oxidized phospholipids in cancer cells
Oxidized phospholipids generate apoptotic
blebs in melanoma cells
Cancer is a complex disease characterized by genetic
mutations that lead to uncontrolled cell growth and
spread of abnormal cells. One in every three cancers
diagnosed is skin cancer, which is skin growth of
melanocytic and non-melanocytic cells with
differing causes and varying degrees of malignancy.
Melanomas which derive from pigment-producing
melanocytes in the basal layer of the epidermis
represent the most dangerous form of skin cancer
and although not being the most common skin
cancer type, they are responsible for most skin
cancer deaths. These tumors have a high chance of
metastasizing and becoming lethal. Surgical removal
of the tumor is only possible at a very early stage,
and chemotherapy as an overall strategy is not very
effective in treating melanomas. Only 15 % to 20 % of patients respond to chemotherapy
which typically works for less than a year and has little or no effect on survival time. In
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