Exp Clin Endocrinol Diabetes 2014; 122 - OP6_29
DOI: 10.1055/s-0034-1372004

Anti-cancer potential of MAPK pathway inhibition in paragangliomas – effect of different statins on mouse pheochromocytoma cells

S Fliedner 1, 2, T Engel 1, 3, N Lendvai 1, U Shankavaram 4, S Nölting 1, 5, R Wesley 6, A Elkalouhn 7, H Ungefroren 2, H Lehnert 2, H Timmers 3, K Pacak 1
  • 1Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology, Bethesda, United States
  • 2University Medical Center Schleswig-Holstein, 1st Department of Medicine, Lübeck, Germany
  • 3Radboud University Nijmegen Medical Centre, Nijmegen, Department of Endocrinology, Radboud, Netherlands
  • 4National Cancer Institute, Radiation Oncology Branch, Bethesda, United States
  • 5William Harvey Research Institute and Barts Cancer Institute, Barts and the London School of Medicine, Queen Mary University of London, Department of Endocrinology, London, United Kingdom
  • 6National Institutes of Health, Warren G. Magnuseon Clinical Center, Bethesda, United States
  • 7National Human Genome Research Institute, Cancer Genetics Branch, Bethesda, United States

To date, malignant pheochromocytomas and paragangliomas (PHEOs/PGLs) cannot be effectively cured. New 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 many 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 indicated that certain aspects of MAPK-signaling are active in SDHB PHEOs/PGLs, which suggests that inhibition by statin treatment could be beneficial.

Moreover, we aimed to assess whether the anti-proliferative effect of lovastatin on MPC and MTT may be equaled or exceeded by fluvastatin, simvastatin, atorvastatin, pravastatin, or rosuvastatin. Simvastatin and fluvastatin decreased cell proliferation most effectively and the more aggressive MTT cells appeared more sensitive.

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 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, lipophylic statins may present a promising therapeutic option for treatment of aggressive human paragangliomas by inducing apoptosis and inhibiting tumor spread.