Anti-cancer potential of MAPK pathway inhibition in paragangliomas-effect of different statins on mouse pheochromocytoma cells.
To date, malignant pheochromocytomas and paragangliomas (PHEOs/PGLs) cannot be effectively cured and thus novel treatment strategies are urgently needed. Lovastatin has been shown to effectively induce apoptosis in mouse PHEO cells (MPC) and the more aggressive mouse tumor tissue-derived cells (MTT), which was accompanied by decreased phosphorylation of mitogen-activated kinase (MAPK) pathway players. The MAPK pathway plays a role in numerous aggressive tumors and has been associated with a subgroup of PHEOs/PGLs, including K-RAS-, RET-, and NF1-mutated tumors. Our aim was to establish whether MAPK signaling may also play a role in aggressive, succinate dehydrogenase (SDH) B mutation-derived PHEOs/PGLs. Expression profiling and western blot analysis indicated that specific aspects of MAPK-signaling are active in SDHB PHEOs/PGLs, suggesting that inhibition by statin treatment could be beneficial. Moreover, we aimed to assess whether the anti-proliferative effect of lovastatin on MPC and MTT differed from that exerted by fluvastatin, simvastatin, atorvastatin, pravastatin, or rosuvastatin. Simvastatin and fluvastatin decreased cell proliferation most effectively and the more aggressive MTT cells appeared more sensitive in this respect. Inhibition of MAPK1 and 3 phosphorylation following treatment with fluvastatin, simvastatin, and lovastatin was confirmed by western blot. Increased levels of CASP-3 and PARP cleavage confirmed induction of apoptosis following the treatment. At a concentration low enough not to affect cell proliferation, spontaneous migration of MPC and MTT was significantly inhibited within 24 hours of treatment. In conclusion, lipophilic statins may present a promising therapeutic option for treatment of aggressive human paragangliomas by inducing apoptosis and inhibiting tumor spread.
Section on Medical Neuroendocrinology, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America; 1st Department of Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany.
Stephanie M J
SM
Fliedner
Section on Medical Neuroendocrinology, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America; Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Tobias
T
Engel
Section on Medical Neuroendocrinology, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
Nikoletta K
NK
Lendvai
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Uma
U
Shankavaram
Section on Medical Neuroendocrinology, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America; Department of Endocrinology, William Harvey Research Institute and Barts Cancer Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
Svenja
S
Nölting
Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland, United States of America.
Robert
R
Wesley
Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Abdel G
AG
Elkahloun
1st Department of Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany.
Hendrik
H
Ungefroren
1st Department of Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany.
Angela
A
Oldoerp
Pompano Beach, Florida, United States of America.
Gary
G
Lampert
1st Department of Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany.
Hendrik
H
Lehnert
Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Henri
H
Timmers
Section on Medical Neuroendocrinology, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
Karel
K
Pacak
D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009363:Neoplasm Proteins