Bilirubin inhibits tumor cell growth via activation of ERK.
Bilirubin for decades was considered a potentially toxic waste product of heme degradation until the discovery that it is a potent antioxidant. Accumulating data from observations in humans and experimental studies indicate that the bile pigment may be protective against certain diseases. Based on our own observations that bilirubin induces cell cycle arrest in abnormally proliferating vascular smooth muscle cells and clinical observations describing a lesser incidence of cancer in healthy individuals with high normal or slightly elevated serum bilirubin levels, we hypothesized that bilirubin might suppress tumor cell proliferation in vitro and in vivo. As possible effectors we analyzed key proteins that are involved in cell cycle progression and apoptosis. In vivo, tumor growth was assessed in BALB/c nude mice bearing HRT-18 colon cancer xenografts that were treated with bilirubin. In vitro, we investigated the effect of bilirubin on various cell lines and the signaling pathways involved in bilirubin action on tumor cell proliferation in HRT-18 cells using western blots. Bilirubin potently inhibited tumor cell proliferation in vivo and acted cytostatic and pro-apoptotic in vitro. The signaling cascades responsible for this action involved induction of p53, p27, hypophosphorylation of the retinoblastoma tumor suppressor protein as well as caspase activation. These effects were dependent on ERK 1/2. Our study demonstrates that bilirubin may play a role in the defense against cancer by interfering with pro-cancerogenic signaling pathways.
Ollinger
Robert
R
Department of General and Transplant Surgery, D. Swarovski Research Lab, Innsbruck Medical University, Innsbruck, Austria. robert.oellinger@i-med.ac.at
Kogler
Pamela
P
Troppmair
Jakob
J
Hermann
Martin
M
Wurm
Martin
M
Drasche
Astrid
A
Königsrainer
Ingmar
I
Amberger
Albert
A
Weiss
Helmut
H
Ofner
Dietmar
D
Bach
Fritz H
FH
Margreiter
Raimund
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001663:Bilirubin / Q000494:pharmacology / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D054697:Cytostatic Agents / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000502:physiology
D054697:Cytostatic Agents; D025521:Tumor Suppressor Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001663:Bilirubin